Kinase inhibitors

ABSTRACT

Compounds of formula (I): 
                         
wherein R 2 , W, A, Y, and R 1  are as defined in the specification, and pharmaceutically acceptable salts thereof, are p38 MAPK inhibitors, and are useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.11192894.1, filed on Dec. 9, 2011 and European Patent Application No.12187932.4, filed on Oct. 10, 2012, both of which are incorporatedherein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds and compositions that are p38MAPK inhibitors, and which are useful as anti-inflammatory agents in thetreatment of, inter alia, diseases of the respiratory tract. The presentinvention also relates to the treatment and/or prevention of diseases ofthe respiratory tract.

2. Discussion of the Background

Mitogen activated protein kinases (MAPK) constitute a family ofproline-directed serine/threonine kinases that activate their substratesby dual phosphorylation. There are four known human isoforms of p38 MAPkinase, p38α, p38β, p38γ, and p38δ. The p38 kinases, which are alsoknown as cytokine suppressive anti-inflammatory drug binding proteins(CSBP), stress activated protein kinases (SAPK) and RK, are responsiblefor phosphorylating (see Stein et al., Ann. Rep. Med. Chem., 1996, 31,289-298, which is incorporated herein by reference in its entirety) andactivating transcription factors (such as ATF-2, MAX, CHOP and C/ERPb)as well as other kinases (such as MAPKAP-K2/3 or MK2/3), and arethemselves activated by physical and chemical stress (e.g. UV, osmoticstress), pro-inflammatory cytokines and bacterial lipopolysaccharide(LPS) (see Herlaar E. & Brown Z., Molecular Medicine Today, 1999, 5,439-447, which is incorporated herein by reference in its entirety). Theproducts of p38 phosphorylation have been shown to mediate theproduction of inflammatory cytokines, including tumor necrosis factoralpha (TNF α) and interleukin-(IL-)-1, and cyclooxygenase-2 (COX-2).IL-1 and TNFα are also known to stimulate the production of otherproinflammatory cytokines such as IL-6 and IL-8.

IL-1 and TNFα are biological substances produced by a variety of cells,such as monocytes or macrophages. IL-1 has been demonstrated to mediatea variety of biological activities thought to be important inimmunoregulation and other physiological conditions such as inflammation(see, e.g. Dinarello et al., Rev. Infect. Disease, 1984, 6, 51, which isincorporated herein by reference in its entirety). Excessive orunregulated TNF production (particularly TNFα) has been implicated inmediating or exacerbating a number of diseases, and it is believed thatTNF can cause or contribute to the effects of inflammation in general.IL-8 is a chemotactic factor produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and keratinocytes.Its production from endothelial cells is induced by IL-1, TNF, orlipopolysaccharide (LPS). IL-8 stimulates a number of functions invitro. It has been shown to have chemoattractant properties forneutrophils, T-lymphocytes and basophils. Increase in IL-8 production isalso responsible for chemotaxis of neutrophils into the inflammatorysite in vivo.

Inhibition of signal transduction via p38, which in addition to IL-1,TNF and IL-8 described above is also required for the synthesis and/oraction of several additional pro-inflammatory proteins (e.g., IL-6,GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highlyeffective mechanism for regulating the excessive and destructiveactivation of the immune system. This expectation is supported by thepotent and diverse anti-inflammatory activities described for p38 kinaseinhibitors (see Badger et al., J. Pharm. Exp. Thera., 1996, 279,1453-1461; Griswold et al, Pharmacol. Comm., 1996, 7, 323-229, which areincorporated herein by reference in their entireties). In particular,p38 kinase inhibitors have been described as potential agents fortreating rheumatoid arthritis. In addition to the links between p38activation and chronic inflammation and arthritis, there is also dataimplicating a role for p38 in the pathogenesis of airway diseases inparticular COPD and asthma. Stress stimuli (including tobacco smoke,infections or oxidative products) can cause inflammation within the lungenvironment. Inhibitors of p38 have been shown to inhibit LPS andovalbumin induced airway TNF-α IL-1β, IL-6, IL-4, IL-5 and IL-13 (seeHaddad et al, Br. J. Pharmacol., 2001, 132 (8), 1715-1724; Underwood etal, Am. J. Physiol. Lung Cell. Mol. 2000, 279, 895-902; Duan et al.,2005 Am. J. Respir. Crit. Care Med., 171, 571-578; Escott et al Br. J.Pharmacol., 2000, 131, 173-176; Underwood et al., J. Pharmacol. Exp.Ther. 2000, 293, 281-288, which are incorporated herein by reference intheir entireties). Furthermore, they significantly inhibit neutrophiliaand the release of MMP-9 in LPS, ozone or cigarette smoke animal models.There is also a significant body of preclinical data highlighting thepotential benefits of inhibition of the p38 kinase that could berelevant in the lung (see Lee et al., Immunopharmacology, 2000, 47,185-200, which is incorporated herein by reference in its entirety).Thus, therapeutic inhibition of p38 activation may be important in theregulation of airway inflammation.

The implication of the p38MAPK pathway in various diseases has beenreviewed by P. Chopra et al. (Expert Opinion on Investigational Drugs,2008, 17(10), 1411-1425, which is incorporated herein by reference inits entirety).

Known P38 kinase inhibitors have been reviewed by G. J. Hanson (ExpertOpinions on Therapeutic Patents, 1997, 7, 729-733) J Hynes et al.(Current Topics in Medicinal Chemistry, 2005, 5, 967-985), C. Dominguezet al (Expert Opinions on Therapeutics Patents, 2005, 15, 801-816) andL. H. Pettus & R. P. Wurtz (Current Topics in Medicinal Chemistry, 2008,8, 1452-1467), which are incorporated herein by reference in theirentireties. P38 kinase inhibitors containing a triazolopyridine motifare known in the art, see for example WO 2007/091152, WO 2004/072072,and WO 2006/018727, which are incorporated herein by reference in theirentireties.

International Patent Application WO 2010/094956 disclosestriazolopyridine derivatives of formula (I) as being p38 MAP kinaseinhibitors:

In such compounds, A represents an optionally substituted divalentarylene radical, an heteroarylene radical, a (C₃-C₆) divalentcycloalkylene radical having 5 or 6 ring atoms or a pyperidinyleneradical. The compounds are said to be useful in as anti-inflammatoryagents in the treatment of diseases of the respiratory tract.

However, there remains a need for improved p38 MAP kinase inhibitors.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide noveland potent p38 mitogen activated protein kinase inhibitors.

It is another object of the present invention to provide novel andpotent p38 mitogen activated protein kinase inhibitors which are usefulin the treatment of inflammatory and obstructive diseases of therespiratory tract.

It is another object of the present invention, to provide novel andpotent p38 mitogen activated protein kinase inhibitors which show anappropriate developability profile on inhalatory administration toeffectively treat respiratory obstructive or inflammatory diseases. Itis to be understood that such profile may be achieved in a number ofdifferent ways by modulation of specific properties; by way of example,it could be achieved by administration of a low effective dose of thedrug thus limiting side effects or via a long duration of action in thelungs which may reduce the frequency of administration.

It is another object of the present invention to provide novel methodsof treating certain diseases and conditions by administering such a p38mitogen activated protein kinase inhibitor.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the compounds of formula (I) are useful as p38 mitogen activatedprotein kinase inhibitors.

Thus, the present invention provides a compound of formula (I), or apharmaceutically acceptable salt thereof:

wherein;

W is a heteroatom selected from N or O, wherein N is substituted withhydrogen, C₁-C₆ alkyl, or C₃-C₅-cycloalkyl;

Y is selected from the group consisting of: a group —S(O)_(p)— wherein pis 0, 1, or 2; a group —O(CR³R⁴)_(n)—; a group —(CR⁵R⁶)_(n)—; a group—NR⁷—; a group —OC(O)—; a group —OC(O)NH—; and a group —OC(O)O—;

R³, R⁴, R⁵, and R⁶ are each independently hydrogen, fluorine, or C₁-C₆alkyl; or, respectively, R³ and R⁴, or R⁵ and R⁶ may form, together withthe carbon atom to which they are attached, a 3-6 membered saturatedcarbocyclic monocyclic ring optionally substituted by a group C₁-C₆alkyl, hydroxyl, or halo;

n is 0, 1, 2, or 3;

R⁷ is hydrogen, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, wherein such C₁-C₆alkyl, or C₃-C₇ cycloalkyl are optionally substituted by a group C₁-C₃alkyl, C₃-C₆ cycloalkyl, hydroxyl, cyano, or halo;

R¹ is a group selected from (IIa) to (IIc):

wherein

R⁸ is —(C₁-C₆alkylene)-NR^(A)R^(B), —(C₃-C₇cycloalkylene)-NR^(A)R^(B),—NR^(A)R^(B), —N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B), or —R^(C);

R^(A) and R^(B) are at each occurrence independently hydrogen, C₁-C₆alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, C₃-C₇ cycloalkyl,—OR^(D), —SR^(D), —NR^(E)R^(F), —CN, or halo; alternatively, R^(A) andR^(B) may form, together with the nitrogen atom to which they areattached, a 5-11 membered saturated monocyclic or bicyclic heterocyclicring system in which the 5-11-membered saturated monocyclic or bicyclicheterocyclic ring is optionally substituted by one or more groups—OR^(D), —CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyland C₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN, or halo; and wherein, optionally,the 5-11-membered saturated monocyclic or bicyclic heterocyclic ringcontains a further heteroatom which is oxygen or nitrogen, said nitrogenatom optionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl whereinany of such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(D), —CN, orhalo;

R^(C) is at each occurrence independently hydrogen, C₁-C₆ alkyl, orC₃-C₆ cycloalkyl, such C₁-C₆ alkyl and C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, OR^(D), —CN, or halo;

R^(D) is at each occurrence independently hydrogen, —CH₃, or —C₂H₅;

R^(E) and R^(F) are at each occurrence independently hydrogen, C₁-C₆alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(D),—SR^(D), —CN, or halo; and/or R^(E) and R^(F) may form, together withthe nitrogen atom to which they are attached, a 5-7 membered saturatedheterocyclic ring system in which the 5-7-membered saturatedheterocyclic ring is optionally substituted by one or more group—OR^(D), —CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyland C₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN, or halo; and wherein, optionally,the said 5-7-membered saturated heterocyclic ring contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl wherein any of such C₁-C₆alkyl or C₃-C₆ cycloalkyl may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, —OR^(D), —CN, or halo;

R²⁶ is hydrogen, —CH₃, or —C₂H₅;

X₁ and X₂ are each independently a group —(CH)— or a nitrogen atom;

R⁹ and R¹⁰ are independently, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenylwhich is optionally substituted, 5- or 6-membered monocyclic heteroarylwhich is optionally substituted, or a radical of formula (IIIa) or(IIIb):

wherein q is 1 or 2; and R²⁴ and R²⁵ are independently hydrogen or C₁-C₆alkyl, or R²⁴ and R²⁵ taken together with the nitrogen to which they areattached form a 6-membered heterocyclic ring optionally containing afurther heteroatom selected from N and O;

R¹¹, R¹², and R¹³ are independently hydrogen, C₁-C₆ alkyl, or halogen;

A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; saidcycloalkylene ring being attached to W and Y, and fused to a phenyl ringor to a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenylor heteroaryl ring being optionally substituted by one or two groupsR²⁷;

R²⁷ is at each occurrence independently selected from the groupconsisting of: C₁-C₆ alkyl, halogen, and cyano;

R² is a radical of formula (IVa), (IVb) or (IVc):

wherein

R¹⁴ is selected from the group consisting of —F, —CH₂OMe, and —CF₂CF₃;

R¹⁵ and R¹⁶ are independently —CH₃ or —C₂H₅;

R¹⁷ is selected from the group consisting of: lone electron pair,hydrogen, —CF₃, —NR^(E1)R^(F1), —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl, or heteroaryl wherein any of such—(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), aryl, or heteroaryl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, orhalo; or

R¹⁷ is a group of formula (V):

wherein

R²⁰ is selected from the group consisting of —F, —CH₃, —C₂H₅, —CH₂OH,—CH₂OMe, —CF₂CF₃, —CH₂SCH₃, —SCH₃, and —SC₂H₅;

R²¹ is —CH₃ or —C₂H₅;

or

R²⁰ and R²¹ as defined above may form, together with the carbon atom towhich they are attached, a 3-7-membered monocyclic ring;

R^(E1) and R^(F1) are each independently C₁-C₆ alkyl optionallysubstituted by a group C₁-C₃ alkyl, —OR^(G), —CN, or halo;alternatively, R^(E1) and R^(F1) may also form, together with thenitrogen atom to which they are attached, a 5-11-membered saturatedmonocyclic or bicyclic heterocyclic ring system in which the said5-11-membered saturated monocyclic or bicyclic heterocyclic ring isoptionally substituted by one or more group —OR^(G), —CN, halo, C₁-C₆alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(G),—CN, or halo; and wherein, optionally, the 5-11-membered saturatedmonocyclic or bicyclic heterocyclic ring contains a further heteroatomwhich is oxygen or nitrogen, said nitrogen atom optionally substitutedby C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R^(G) is independently at each occurrence hydrogen, —CH₃, or —C₂H₅;

R¹⁸ is selected from the group consisting of lone electron pair,hydrogen, aryl, heteroaryl, —(C₁-C₆alkyl), —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), —(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), and(C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl); wherein any of such aryl,heteroaryl, —(C₁-C₆alkyl), —(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), or (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl) may be optionally substituted by a group —CN, —OH, halo,—COOR^(M), C₁-C₆alkyl, C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl), —S—(C₃-C₆cycloalkyl),—NR^(H)R^(J), —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J)),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl); wherein any of suchC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl), and(C₅-C₇heterocycloalkyl)carbonyl portion in the above listed groups maybe optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), or halo;

R^(H) and R^(J) are at each occurrence independently hydrogen, C₁-C₆alkyl, or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, —OR^(M), —CN, or halo;alternatively, R^(H) and R^(J) may also form, together with the nitrogenatom to which they are attached, a 5-11 membered saturated monocyclic orbicyclic heterocyclic ring system in which the 5-11-membered saturatedmonocyclic or bicyclic heterocyclic ring is optionally substituted byone or more group —OR^(M), —CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl,such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by agroup C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M), —CN, or halo; and wherein,optionally, the 5-11-membered saturated monocyclic or bicyclicheterocyclic ring contains a further heteroatom which is oxygen ornitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkylmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), —CN, or halo; and/or R^(H) and R^(J) may be linked to onecarbon atom of the —(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)-portion ofthe group linked to the nitrogen to which they are connected to form asaturated cycle of up to 6 ring atoms;

R^(L) is at each occurrence independently hydrogen, C₁-C₆ alkyl, orC₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), —CN, or halo.

R^(M) is at each occurrence independently hydrogen, C₁-C₄ alkyl, orC₃-C₆ cycloalkyl, such C₁-C₄ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group hydroxyl, —CN, or halo;

R¹⁹ is selected from the group consisting of hydrogen, —CF₃,—NR^(E)R^(F), —(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), aryl, andheteroaryl wherein any of such —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl, or heteroaryl may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, or halo; or

R¹⁹ is a group of formula (V):

wherein R²⁰, R²¹, R^(E) and R^(F) are as above defined;

z¹, z², z³, and z⁴ are independently selected in the group consistingof: C, N, S, O, a group —CH—, and a group —NH—, in such a combinationthat the resulting ring formed is an aromatic system;

T is —N═ or —CR²⁸═;

R²⁸ is H, halo, —CH₃, or —CN;

R²² is H, halo, —CH₃, or —CN;

with the provisos that:

when z¹=—CH—, z²=—C—, z³=—O—, z⁴=—N—, R¹⁸ is an electron lone pair, R¹⁷is a group of formula (V), and R²¹ is —CH₃ or —C₂H₅;

then R²⁰ is —F, —CH₂OMe or —CF₂CF₃;

when z¹=—CH—, z²=—C—, z³=—N—, z⁴=—N—, R¹⁷ is a group of formula (V), R²¹is —CH₃ or —C₂H₅ and R²⁰ is —CH₃, —C₂H₅; —CH₂OH, —CH₂SCH₃, —SCH₃, or—SC₂H₅, and R₁₈ is a phenyl ring;

then such phenyl ring is substituted by a group which is selected fromthe group consisting of —CN, —COOR^(M), C₃-C₆cycloalkyl,—O—(C₁-C₆alkyl), —O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl),—S—(C₃-C₆cycloalkyl), —NR^(H)R^(J),—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S—(C₂-C₆alkylene)-NR^(H)R^(J), —S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)NR^(H)R^(J),—C(O)NR^(H)R^(J), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), SR^(L),—(C₃-C₇heterocycloalkyl), —(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), and(C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl); wherein any of suchC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl), and(C₅-C₇heterocycloalkyl)carbonyl portion in the above listed groups maybe optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), or halo;

or such phenyl ring is substituted by a group which is—(C₁-C₆alkylene)-NR^(H)R^(J) or —O—(C₂-C₆alkylene)-NR^(H)R^(J) whereinR^(H) and R^(J), which are not both hydrogen, are at each occurrenceindependently hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl, such C₁-C₆alkyl or C₃-C₆ cycloalkyl being substituted by a group —OR^(M), —CN, orhalo; alternatively, R^(H) and R^(J) may form, together with thenitrogen atom to which they are attached, a 5-11 membered saturatedheterocyclic monocyclic or bicyclic ring system in which the5-11-membered saturated heterocyclic monocyclic or bicyclic ring issubstituted by one or more groups —OR^(M), —CN, halo, C₁-C₆ alkyl, orC₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M), —CN, orhalo; and wherein, optionally, the 5-11-membered saturated monocyclic orbicyclic heterocyclic ring contains a further heteroatom which is oxygenor nitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkylmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), —CN, or halo;

or such phenyl ring is substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(M), or halo;

or such phenyl ring is substituted by a group —OR^(L) wherein R^(L) isC₁-C₆ alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkylbeing optionally substituted by a group C₁-C₃ alkyl, —OR^(M), —CN, orhalo;

or such phenyl ring is substituted by a group C₁-C₆ alkyl which issubstituted by a group C₃-C₇ cycloalkyl, OR^(M), or halo; and

when R¹⁹ is a morpholine ring and T is —CR²⁸═ or —N═;

then R²², if present at position ortho to group T of the aromatic ring,is —CH₃ or —CN.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable carriers and/or excipients. Particularlypreferred are compositions adapted for inhalation for pulmonaryadministration.

The compounds of the present invention are inhibitors of p38 mitogenactivated protein kinase (“p38 MAPK,” “p38 kinase,” or “p38”), includingp38α kinase, and are inhibitors of cytokine and chemokine productionincluding TNFα and IL-8 production. They have a number of therapeuticapplications, in the treatment of inflammatory diseases, particularlyallergic and non-allergic airways diseases, more particularlyobstructive or inflammatory airways diseases such as chronic obstructivepulmonary disease (“COPD”) and asthma. They are therefore particularlysuited for pulmonary delivery, by inhalation by nose or mouth.

It is believed that the compounds of the present invention can be usedto treat p38 mediated diseases such as: chronic obstructive pulmonarydisease (COPD), asthma, chronic or acute bronchoconstriction,bronchitis, acute lung injury and bronchiectasis, pulmonary arteryhypertension, tuberculosis, lung cancer, inflammation generally (e.g.inflammatory bowel disease), arthritis, neuroinflammation, pain, fever,fibrotic diseases, pulmonary disorders and diseases (e.g., hyperoxicalveolar injury), cardiovascular diseases, post-ischemic reperfusioninjury and congestive heart failure, cardiomyopathy, stroke, ischemia,reperfusion injury, renal reperfusion injury, brain edema, neurotraumaand brain trauma, neurodegenerative disorders, central nervous systemdisorders, liver disease and nephritis, gastrointestinal conditions,ulcerative diseases, Crohn's disease, ophthalmic diseases,ophthalmological conditions, glaucoma, acute injury to the eye tissueand ocular traumas, diabetes, diabetic nephropathy, skin-relatedconditions, myalgias due to infection, influenza, endotoxic shock, toxicshock syndrome, autoimmune disease, graft rejection, bone resorptiondiseases, multiple sclerosis, psoriasis, eczema, disorders of the femalereproductive system, pathological (but non-malignant) conditions, suchas hemangiomas, angiofibroma of the nasopharynx, and avascular necrosisof bone, benign and malignant tumors/neoplasia including cancer,leukaemia, lymphoma, systemic lupus erythematosus (SLE), angiogenesisincluding neoplasia, haemorrhage, coagulation, radiation damage, and/ormetastasis. Chronic release of active TNF can cause cachexia andanorexia, and TNF can be lethal. TNF has also been implicated ininfectious diseases. These include, for example, malaria, mycobacterialinfection and meningitis. These also include viral infections, such asHIV, influenza virus, and herpes virus, including herpes simplex virustype-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus(CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV7), human herpesvirus-8(HHV-8), pseudorabies and rhinotracheitis, among others.

Thus, in another aspect, the present invention provides methods for thetreatment of diseases or conditions which benefit from inhibition of p38MAP kinase activity. The treatment of obstructive or inflammatoryairways diseases is a preferred use. All forms of obstructive orinflammatory airways diseases are potentially treatable with thecompounds of the present invention, in particular an obstructive orinflammatory airways disease that is a member selected from the groupconsisting of chronic eosinophilic pneumonia, asthma, COPD, COPD thatincludes chronic bronchitis, pulmonary emphysema or dyspnea associatedor not associated with COPD, COPD that is characterized by irreversible,progressive airways obstruction, adult respiratory distress syndrome(ARDS), exacerbation of airways hyper-reactivity consequent to otherdrug therapy and airways disease that is associated with pulmonaryhypertension, chronic inflammatory diseases including cystic fibrosis,broncietasis and pulmonary fibrosis (Idiopathic). Efficacy isanticipated when p38 kinase inhibitors are administered either locallyto the lung (for example by inhalation and intranasal delivery) or viasystemic routes (for example, oral, intravenous and subcutaneousdelivery).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein, the terms “halogen” or “halo” include fluorine,chlorine, bromine, and iodine atoms.

As used herein, the term “C_(x)-C_(y)alkyl” wherein x and y areintegers, refers to a straight or branched chain alkyl radical havingfrom x to y carbon atoms. Thus, when x is 1 and y is 6, for example, theterm includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, and n-hexyl.

As used herein, the term “C_(x)-C_(y)alkylene” wherein x and y areintegers, refers to a C_(x)-C_(y)alkyl radical having in total twounsatisfied valencies, such as a divalent methylene or ethylene radical.

As used herein, the term “carbocyclic” ring refers to a mono-, bi-, ortricyclic radical having up to 16 ring atoms, all of which are carbon,and includes aryl and cycloalkyl.

As used herein, the term “C_(z)-C_(k)cycloalkyl” wherein z and k areintegers refers to a monocyclic saturated carbocyclic radical havingfrom z to k carbon atoms and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Comprised within the scope of the term “C_(z)-C_(k)cycloalkyl” are thoseradicals having two unsatisfied valencies on the same carbon atom whichwill link to any C_(x)-C_(y)alkyl, C_(x)-C_(y)alkylene,C_(z)-C_(k)cycloalkyl, C_(z)-C_(k)cycloalkylene,C_(z)-C_(k)heterocycloalkyl,C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl,C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl or(C_(z)-C_(k))heterocycloalkylcarbonyl group by replacement of twohydrogen atoms placed on the same carbon. In such circumstances, thisradical forms a gem-disubstituted or spyro system together with theC_(x)-C_(y)alkyl, C_(x)-C_(y)alkylene C_(z)-C_(k)cycloalkylC_(z)-C_(k)cycloalkylene, C_(z)-C_(k)heterocycloalkyl,C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl,C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl, or(C_(z)-C_(k))heterocycloalkylcarbonyl group it is linked to.

The term “C_(z)-C_(k)cycloalkylene radical” refers to aC_(z)-C_(k)cycloalkyl radical having two unsatisfied valencies ondifferent carbon atoms in the cycle, as such as 1,3-cyclopentylene,1,4-cyclohexylene and 1,4-cycloheptylene as follows:

As used herein, the unqualified term “aryl” refers to a mono- orbi-cyclic carbocyclic aromatic radical, and includes radicals having twomonocyclic carbocyclic aromatic rings which are directly linked by acovalent bond. Illustrative of such radicals are phenyl, biphenyl, andnapthyl.

As used herein, the unqualified term “heteroaryl” refers to a mono- orbi-cyclic aromatic radical containing one or more heteroatoms selectedfrom S, N, and O, and includes radicals having two such monocyclicrings, or one such monocyclic ring and one monocyclic aryl ring, whichare fused through a common bond. Illustrative examples of 5,6-memberedheteroaryl are: are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl. Illustrative examples of 8,10-memberedheteroaryl are: benzothienyl, benzofuryl, benzimidazolyl,benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,benzotriazolyl, indolyl, and indazolyl.

As used herein, the unqualified term “heterocyclyl” or “heterocyclic”and relates to a saturated mono-, bi-, or tri-cyclic non-aromaticradical containing one or more heteroatoms selected from S, N, and O. Inparticular, the term “C_(z)-C_(k)heterocycloalkyl” refers to monocyclic(C_(z)-C_(k))cycloalkyl groups, in which at least one ring carbon atomis replaced by a heteroatom (e.g. N, NH, S, or O). Examples of(C_(z)-C_(k))heterocycloalkyl include pyrrolidinyl, thiazolidinyl,piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl.

By analogy, the term “C_(z)-C_(k)heterocycloalkylene”, refers to adivalent C_(z)-C_(k)heterocycloalkyl radical, whereinC_(z)-C_(k)heterocycloalkyl is as above defined.

The term “C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” refers to theabove “C_(x)-C_(y)alkyl” group wherein one or more hydrogen atoms arereplaced by one or more “C_(z)-C_(k)heterocycloalkyl” groups. Comprisedwithin the scope of the term“C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” are systems where twohydrogen atoms linked to the same carbon atom in “C_(x)-C_(y)alkyl”group are replaced by one “C_(z)-C_(k)heterocycloalkyl” group. Suchradical thus form a gem-disubstituted“C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” system, such as a1,2-dimethyl-pyrrolidin-2-yl radical.

The term “C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl” refers tothe above “C_(z)-C_(k) cycloalkyl” group wherein one or more hydrogenatoms are replaced by one or more “C_(z)-C_(k)heterocycloalkyl” groups.

The expression “(C_(z)-C_(k))cycloalkylcarbonyl” refers to(C_(z)-C_(k))cycloalkyl-CO-groups wherein the group“(C_(z)-C_(k))cycloalkyl” has the meaning above defined.

The expression “(C_(z)-C_(k))heterocycloalkylcarbonyl” refers to(C_(z)-C_(k))heterocycloalkyl-CO— groups wherein the group“(C_(z)-C_(k))heterocycloalkyl” has the meaning above defined.

Unless otherwise specified in the context in which it occurs, the term“substituted” as applied to any aryl or heteroaryl moiety herein meanssubstituted with at least one substituent, for example selected from(C₁-C₆)alkyl, (C₁-C₆) fluoroalkyl, (C₁-C₆)alkoxy (includingmethylenedioxy and ethylenedioxy substitution on adjacent carbon atomsof an aromatic ring), (C₁-C₆)fluoroalkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,benzyloxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy,benzyloxy-(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkylthio, mercapto,mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, cyclopropyl, halo (includingfluoro and chloro), O-benzyl, nitro, nitrile (cyano), —COOH, tetrazolyl,—COOR^(a), —COR^(b), —SO₂R^(a), —CONH₂, —SO₂NH₂, —CONHR^(a),—SO₂NHR^(a), —CONR^(a)R^(b), —SO₂NR^(a)R^(b), —NH₂, —NHR^(a),—NR^(a)R^(b), —OCONH₂, —OCONHR^(a), —OCONR^(a)R^(b), —NHCOR^(a),—NHCOOR^(a), —NR^(b)COOR^(a) —NHSO₂OR^(a), —NR^(b)SO₂OR^(a), —NHCONH₂,—NR^(a)CONH₂, —NHCONHR^(b), —NR^(a)CONHR^(b), —NHCONR^(a)R^(b), or—NR^(a)CONR^(a)R^(b) wherein R^(a) and R^(b) are independently a(C₁-C₄)alkyl group, or R^(a) and R^(b) when attached to the samenitrogen may form, together with that nitrogen, a cyclic amino groupsuch as a morpholinyl, piperidinyl, or piperazinyl group. An “optionalsubstituent” may be one of the substituent groups encompassed in theabove description.

Compounds of the invention may exist in one or more geometrical,optical, enantiomeric, diastereomeric, and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. Unless otherwise stated a referenceto a particular compound includes all such isomeric forms, includingracemic and other mixtures thereof. Where appropriate such isomers canbe separated from their mixtures by the application or adaptation ofknown methods (e.g. chromatographic techniques and recrystallisationtechniques). Where appropriate such isomers may be prepared by theapplication of adaptation of known methods (e.g. asymmetric synthesis).

Throughout the specification the use of an asterisk “*” in thedefinition of a structural formula, indicates the point of attachmentfor the radical group to the rest of the molecule.

As used herein the term “salt” includes base addition, acid addition,and ammonium salts. As briefly mentioned above, compounds of theinvention which are acidic can form salts, including pharmaceuticallyacceptable salts, with bases such as alkali metal hydroxides, e.g.sodium and potassium hydroxides; alkaline earth metal hydroxides e.g.calcium, barium and magnesium hydroxides; with organic bases e.g.N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane,L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine, and the like.Those compounds of the invention which are basic can form salts,including pharmaceutically acceptable salts with inorganic acids, e.g.with hydrohalic acids such as hydrochloric or hydrobromic acids,sulphuric acid, nitric acid, or phosphoric acid and the like, and withorganic acids e.g. with formic, acetic, trifluoroacetic, tartaric,succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic,p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, andmandelic acids, and the like. Those compounds (1) which have a basicnitrogen can also form quaternary ammonium salts with a pharmaceuticallyacceptable counter-ion such as ammonium, chloride, bromide, acetate,formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bissulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.For a review on salts, see Handbook of Pharmaceutical Salts: Properties,Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002), which is incorporated herein by reference in its entirety.

It is expected that compounds of the invention may be prepared in theform of hydrates, and solvates. Any reference herein, including theclaims herein, to “compounds with which the invention is concerned,” or“compounds of the invention,” or “the present compounds,” and the like,includes reference to salts, hydrates, and solvates of such compounds.The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Individual compounds of the present invention may exist in severalpolymorphic forms and may be obtained in different crystal or co-crystalhabits, and they are intended to be included within the meaning of theterm “compounds of the invention.”

The compounds of the present invention may also be administered in theform of prodrugs thereof. Thus certain derivatives of the compoundswhich may be active in their own right or may have little or nopharmacological activity themselves can, when administered into or ontothe body, be converted into compounds of the invention having thedesired activity, for example, by hydrolytic cleavage. Such derivativesare referred to as ‘prodrugs’. Further information on the use ofprodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14,ACS Symposium Series (T. Higuchi and V. J. Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association; C. S. Larsen and J. Østergaard, Design andapplication of prodrugs, In Textbook of Drug Design and Discovery,3^(rd) Edition, 2002, Taylor and Francis), which are incorporated hereinby reference in their entireties.

Prodrugs in accordance with the present invention can, for example, beproduced by replacing appropriate functionalities present in thecompounds of formula (I) with certain moieties known to those skilled inthe art as ‘pro-moieties’ as described, for example, in Design ofProdrugs by H. Bundgaard (Elsevier, 1985), which is incorporated hereinby reference in its entirety. Such examples could be a prodrug of acarboxyl group (such as —CO—O—CH₂—O—CO-tBu as used in the pivampicillinprodrug of ampicillin), an amide (—CO—NH—CH₂—NAlk₂), or an amidine(—C(═N—O—CH₃)—NH₂).

It is to be understood that all preferred groups or embodimentsdescribed herebelow for compounds of formula (I) may be combined amongeach other and apply as well to compounds of formula (IA), (IB), (Ia),(Ib) or (Ic) as below defined mutatis mutandis.

In one embodiment, compounds of formula (Ia) are provided, which arecompounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which is linked to group Wand identified with number (1) herebelow, possess the absoluteconfiguration herebelow represented:

In another embodiment, compounds of formula (Ib) are provided, which arecompounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which are linked to groupW and Y and identified, respectively, with numbers (1) and (2)herebelow, possess the absolute configuration herebelow represented:

In a further embodiment, compound of formula (Ic) are provided, whichare compounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which are linked to groupW and Y and identified, respectively, with numbers (1) and (2)herebelow, possess the absolute configuration herebelow represented:

In one embodiment, W is NH or O. In a further embodiment, W is NH.

In one embodiment, Y is a group —S(O)_(p)—, a group —O(CR³R⁴)_(n)—, agroup —(CR⁵R⁶)_(n)—, or a group —NR⁷—; p is zero and n is 0, 1 or 2. Inanother embodiment, Y is —S(O)_(p)— or a group —O(CR³R⁴)_(n) or; p iszero and n is 0 or 1. In a further embodiment, Y is a group—O(CR³R⁴)_(n)— and n is 0.

In one embodiment, R³, R⁴, R⁵, and R⁶ are each independently hydrogen,fluorine, or C₁-C₆ alkyl. In another embodiment, R³, R⁴, R⁵, and R⁶ arehydrogen.

In one embodiment, R⁷ is hydrogen, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl.

In one embodiment, R⁷ is hydrogen.

In one embodiment, A is a divalent cycloalkylene radical having 5 or 6ring atoms; said cycloalkylene ring being attached to W and Y, and fusedto a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ringatoms, and such phenyl or heteroaryl ring being optionally substitutedby one or two groups R²⁴.

In a further embodiment, A is a group selected from the group consistingof:

In a still further embodiment, A is group:

In an additional embodiment, A is group:

In one embodiment, R²⁷ is not present or, if present, is at eachoccurrence independently selected from the group consisting of: C₁-C₂alkyl, —F, —Cl, and cyano; in a further embodiment, R²⁷ is not presentor, if present, is at each occurrence independently methyl or —F. In afurther embodiment, R²⁷ is not present.

In one embodiment, R¹ is a group of formula (IIa):

In one embodiment, R¹¹ hydrogen.

In one embodiment R²⁶ is hydrogen, —CH₃, or —C₂H₅; in anotherembodiment, R²⁶ is hydrogen, or —CH₃; in a further embodiment R²⁶ ishydrogen.

In one embodiment, R⁸ is —(C₁-C₆alkylene)-NR^(A)R^(B), —N(R^(A)R^(B)),—N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B) or —R^(C); in anotherembodiment R⁸ is —R^(C).

In one embodiment, R⁸ is —CH₂—OMe.

In another embodiment, R¹ is a group of formula (IIb):

In one embodiment, X¹ is a nitrogen atom or a group —CH—; in anotherembodiment, X¹ is a nitrogen atom; in another embodiment, X¹ is a group—CH—.

In one embodiment, R¹² hydrogen.

In one embodiment, R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl which isoptionally substituted, 5- or 6-membered monocyclic heteroaryl which isoptionally substituted. In a further embodiment, R⁹ is C₁-C₆ alkyl,C₃-C₆ cycloalkyl. In a still further embodiment, R⁹ is C₁-C₆ alkyl, forexample isopropyl. In another embodiment, R⁹ is phenyl which isoptionally substituted by one or two halogen atoms, for examplechlorine.

In another embodiment, R⁹ is a radical of formula (IIIa) or (IIIb)

In another embodiment, R¹ is a group of formula (IIc):

In one embodiment, X² is a nitrogen atom or a group —CH—; in anotherembodiment, X² is a group —CH—.

In one embodiment, R¹³ hydrogen.

In one embodiment, R¹⁰ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl which isoptionally substituted, 5- or 6-membered monocyclic heteroaryl which isoptionally substituted. In a further embodiment, R¹⁰ is C₁-C₆ alkyl,C₃-C₆ cycloalkyl. In a still further embodiment, R¹⁰ is C₁-C₆ alkyl.

In another embodiment, R¹⁰ is a radical of formula (IIIa) or (IIIb)

In one embodiment, R² is a radical of formula (IVa):

In one embodiment, R¹⁴ is selected in the group consisting of: —F,—CH₂OMe, and —CF₂CF₃.

In one embodiment, R¹⁵ and R¹⁶ are independently —CH₃ or —C₂H₅; inanother embodiment, R¹⁵ and R¹⁶ are —CH₃.

In another embodiment, R² is a radical of formula (IVb):

In one embodiment, R¹⁷ is selected from the group consisting of: loneelectron pair, hydrogen, —CF₃, —NR^(E1)R^(F1), —(C₃-C₆cycloalkyl),—(C₄-C₆heterocycloalkyl), aryl, or heteroaryl wherein any of such—(C₃-C₇cycloalkyl), —(C₄-C₆heterocycloalkyl), aryl, or heteroaryl may beoptionally substituted by a group methyl, isopropyl, or halo. In anotherembodiment, R¹⁷ is selected from the group consisting of: lone electronpair, hydrogen, —CF₃, morpholine, cyclohexyl, phenyl, or pyridyl.

In another embodiment, R¹⁷ is a group of general formula (IV)

In one embodiment, R²⁰ is selected in the group consisting of —F, —CH₃;—CH₂OH, —CH₂OMe, and —CH₂SCH₃; in another embodiment, R²⁰ is selected inthe group consisting of —CH₃, —CH₂OH, and —CH₂OMe. In a furtherembodiment, R²⁰ is —CH₃.

In one embodiment, R²¹ is —CH₃.

In another embodiment, R²⁰ and R²¹ as defined above may form, togetherwith the carbon atom to which they are attached, a cyclohexane orcyclopropyl ring; in a further embodiment, R²⁰ and R²¹ as defined abovemay form, together with the carbon atom to which they are attached, acyclopropyl ring.

In one embodiment, R^(E1) and R^(F1) are each independently C₁-C₃ alkyloptionally substituted by a group C₁-C₂ alkyl, —OR^(G), CN, or halo. Ina further embodiment, R^(E1) and R^(F1) are each independently C₁-C₃alkyl.

In another embodiment, R^(E1) and R^(F1) form, together with thenitrogen atom to which they are attached, a 5-6-membered saturatedmonocyclic or bicyclic ring system optionally containing a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₂ alkyl or C₃-C₇cycloalkyl. In a further embodiment,R^(E1) and R^(F1) form, together with the nitrogen atom to which theyare attached, a morpholine, pyran, furan, piperidine, pyrrolidine, orpiperazine in which, when possible, the nitrogen atom is optionallysubstituted by methyl.

In one embodiment, R¹⁸ is phenyl which is optionally substituted by agroup —CN, OH, halo, COOR^(M), C₁-C₆alkyl, C₃-C₆cycloalkyl,—O—(C₁-C₆alkyl), —O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl),—S—(C₃-C₆cycloalkyl), —NR^(H)R^(J),—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J)),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl), wherein any of suchC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl), and(C₅-C₇heterocycloalkyl)carbonyl portion in the above listed groups maybe optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), or halo.

In another embodiment, R¹⁸ is —(C₁-C₆alkyl) or —(C₃-C₇cycloalkyl).

In one embodiment, z¹=—CH—, z²=C, z³ and z⁴ are N; in anotherembodiment, z¹=O, z²=C, z³ and z⁴ are N; in a further embodiment,z¹=—CH—, z² and z³ are N, and z⁴ is —CH—; in an additional embodiment,z¹=N, z² is C, z³ is N and z⁴ is O; in a still further embodiment, z¹=N,z² is C, z³ is O, and z⁴ is N.

In an additional embodiment, R² is a radical of formula (IVb):

wherein z¹=O, z²=C, z³ is N, z⁴ is N, R¹⁸ is a lone pair, and R¹⁷ is agroup of general formula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃.

In another embodiment, R² is a radical of formula (IVb):

wherein z¹=N, z²=C, z³ is N, z⁴ is O, R¹⁸ is a lone pair, and R¹⁷ is agroup of formula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃.

In an additional embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=N, z³ is N, z⁴ is —C—, R¹⁸ is hydrogen, and R¹⁷ is agroup of general formula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃.

In an additional embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=N, z³ is N, z⁴ is —C—, R¹⁸ is hydrogen, and R¹⁷ is aaryl which is optionally substituted by a group (C₁-C₆)alkyl.

In an additional embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃.

In another embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, R²¹ is —CH₃ and wherein

R¹⁸ is phenyl, which is substituted by a group which is—(C₁-C₆alkylene)-NR^(H)R^(J) or —O—(C₂-C₆alkylene)-NR^(H)R^(J) whereinR^(H) and R^(J), which are not both hydrogen, are at each occurrenceindependently hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein suchC₁-C₆ alkyl or C₃-C₆ cycloalkyl is substituted by a group OR^(M), CN, orhalo; alternatively, R^(H) and R^(J) may form, together with thenitrogen atom to which they are attached, a 5-11 membered saturatedmonocyclic or bicyclic heterocyclic ring system in which the5-11-membered saturated monocyclic or bicyclic ring is substituted byone or more groups OR^(M), CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl,such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by agroup C₁-C₃ alkyl, C₃-C₇cycloalkyl, OR^(M), CN, or halo; and whereinoptionally, the 5-11-membered saturated monocyclic or bicyclicheterocyclic ring contains a further heteroatom which is oxygen ornitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of such alkyl or cycloalkyl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(M),CN, or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(M), or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group C₁-C₆ alkylwhich is substituted by a group C₃-C₇ cycloalkyl, —OR^(M), or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group —CN,—O—(C₁-C₆alkyl), —NR^(H)R^(J), —O—(C₂-C₆alkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —(C₃-C₇heterocycloalkyl), wherein any of suchC₁-C₆alkyl, —(C₂-C₆alkylene)-, —(C₃-C₇heterocycloalkyl), portion in theabove listed groups may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, OR^(M), or halo.

In a further embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃ and R¹⁸ is heteroarylring which is optionally substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is optionally substitutedby a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(M) or halo; or R¹⁸ isheteroaryl ring which is optionally substituted by a group—(C₁-C₆alkylene)-NR^(H)R^(J) or —O—(C₂-C₆alkylene)-NR^(H)R^(J).

In an additional embodiment, R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃ and R¹⁸ is a group—(C₁-C₆alkyl), optionally substituted by a group —OH, halo or—NR^(H)R^(J); or a group (C₅-C₇heterocycloalkyl) or(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) which may be optionally substitutedby a group C₁-C₆ alkyl, halo, or —OH.

In a further embodiment, R² is a radical of formula (IVc):

In one embodiment, R¹⁹ is selected from the group consisting of:hydrogen, —CF₃, —NR^(E)R^(F), —(C₃-C₆cycloalkyl),—(C₃-C₆heterocycloalkyl), aryl, and heteroaryl wherein any of such—(C₃-C₆cycloalkyl), —(C₃-C₆heterocycloalkyl), aryl, or heteroaryl may beoptionally substituted by a group C₁-C₂ alkyl, C₃-C₅ cycloalkyl, orhalo. In another embodiment, R¹⁹ is selected from the group consistingof: hydrogen, —CF₃, morpholine, cyclohexyl, phenyl, or pyridyl whereinany of such morpholine, cyclohexyl, phenyl, or pyridyl may be optionallysubstituted by a group methyl, —F or —Cl.

In another embodiment, R¹⁹ is a group of general formula (V)

In one embodiment, T is —N═. In another embodiment, T is —CR²⁸═.

In one embodiment, R²² is H, F, —Cl, —CH₃, or —CN; in anotherembodiment, R²² is H or F.

In one embodiment, R²³ is H, F, —Cl, —CH₃, or —CN; in anotherembodiment, R²³ is —Cl.

In one embodiment, compounds of formula (IA) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group:

R¹ is a group of formula (IIb):

wherein X¹ is a group —CH—; R¹² hydrogen; R⁹ is C₁-C₆ alkyl, C₃-C₆cycloalkyl, phenyl which is optionally substituted, or 5- or 6-memberedmonocyclic heteroaryl which is optionally substituted;

R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃, and R¹⁸ is a group—(C₁-C₆alkyl), optionally substituted by a group —OH, halo or—NR^(H)R^(J); or a group (C₅-C₇heterocycloalkyl) or(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) which may be optionally substitutedby a group C₁-C₆ alkyl, halo or —OH.

In one embodiment, compounds of formula (IB) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group:

R¹ is a group of formula (IIb):

wherein X¹ is a group —CH—; R¹² is hydrogen; R⁹ is C₁-C₆ alkyl, C₃-C₆cycloalkyl, phenyl which is optionally substituted, or 5- or 6-memberedmonocyclic heteroaryl which is optionally substituted;R² is a radical of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (V)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃; and wherein

R¹⁸ is phenyl, which is substituted by a group which is—(C₁-C₆alkylene)-NR^(H)R^(J) or —O—(C₂-C₆alkylene)-NR^(H)R^(J) whereinR^(H) and R^(J), which are not both hydrogen, are at each occurrenceindependently hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein suchC₁-C₆ alkyl or C₃-C₆ cycloalkyl is substituted by a group OR^(M), CN, orhalo; alternatively, R^(H) and R^(J) may form, together with thenitrogen atom to which they are attached, a 5-11 membered saturatedmonocyclic or bicyclic ring system in which the 5-11-membered saturatedmonocyclic or bicyclic ring is substituted by one or more group OR^(M),CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl, OR^(M), CN, or halo; and wherein optionally, the5-11-membered saturated monocyclic or bicyclic ring contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein any of suchalkyl or cycloalkyl may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, OR^(M), CN, or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(M), or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group C₁-C₆ alkylwhich is substituted by a group C₃-C₇ cycloalkyl, —OR^(M), or halo;

or wherein R¹⁸ is phenyl, which is substituted by a group —CN,—O—(C₁-C₆alkyl), —NR^(H)R^(J), —O—(C₂-C₆alkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —(C₃-C₇heterocycloalkyl), wherein any of suchC₁-C₆alkyl, —(C₂-C₆alkylene)-, —(C₃-C₇heterocycloalkyl), portion in theabove listed groups may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, OR^(M), or halo.

In one embodiment, a compound of formula (I) is selected from the groupconsisting of:

-   1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(2-hydroxyethylsulfanyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(1-p-tolyl-11H-pyrazol-4-yl)-urea;-   1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea,    and-   1-(5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;    or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound of formula (I) is selected from thegroup consisting of:

-   1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(2-hydroxyethylsulfanyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea;-   1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea,    and-   1-(5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-7-fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[(1S,4R)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea;-   1-(1-tert-Butyl-1H-pyrazol-4-yl)-3-[(1S,4R)-7-fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(2-piperidin-1-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-{5-tert-Butyl-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea;    or a pharmaceutically acceptable salt thereof.    Utility.

As mentioned above the compounds of the present invention are p38MAPKinhibitors, and thus may have utility for the treatment of diseases orconditions which benefit from inhibition of the p38 enzyme. Suchdiseases and conditions are known from the literature and several havebeen mentioned above. However, the compounds are generally of use asanti-inflammatory agents, particularly for use in the treatment ofrespiratory disease. In particular, the compounds may be used in thetreatment of chronic obstructive pulmonary disease (COPD), chronicbronchitis, lung fibrosis, pneumonia, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, or smoking-induced emphysema,intrinsic (non-allergic asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, steroid resistant asthma,neutrophilic asthma, bronchitic asthma, exercise induced asthma,occupational asthma and asthma induced following bacterial infection,cystic fibrosis, pulmonary fibrosis and bronchiectasis.

The present invention provides the use of the compounds of the inventionfor the prevention and/or treatment of any disease or condition whichbenefit from inhibition of the p38 enzyme.

In a further aspect the present invention provides the use of compoundsof the invention for the preparation of a medicament for the preventionand/or treatment of any disease or condition which benefit frominhibition of the p38 enzyme.

Moreover the present invention provides methods for prevention and/ortreatment of any disease which benefit from inhibition of the p38enzyme, said method comprises administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of theinvention.

Compositions.

As mentioned above, the compounds with which the invention is concernedare p38 kinase inhibitors, and are useful in the treatment of severaldiseases for example inflammatory diseases of the respiratory tract.Examples of such diseases are referred to above, and include asthma,rhinitis, allergic airway syndrome, bronchitis and chronic obstructivepulmonary disease.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 μg to about 1 mg per kg body weight of a human, preferably 0.1 μg to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases. For thepurpose of the invention, inhaled administration is preferred.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. Orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

However, for treatment of an inflammatory disease of the respiratorytract, compounds of the invention may also be formulated for inhalation,for example as a nasal spray, or dry powder or aerosol inhalers. Fordelivery by inhalation, the active compound is preferably in the form ofmicroparticles. They may be prepared by a variety of techniques,including spray-drying, freeze-drying and micronisation. Aerosolgeneration can be carried out using, for example, pressure-driven jetatomizers or ultrasonic atomizers, preferably using propellant-drivenmetered aerosols or propellant-free administration of micronized activecompounds from, for example, inhalation capsules or other “dry powder”delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebulizer or as an aerosol in a liquidpropellant, for example for use in a pressurized metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂), andHFA-152 (CH₄F₂ and isobutane).

In a preferred embodiment of the present invention, a composition of thepresent invention is in dry powder form, for delivery using a dry powderinhaler (DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, an example is:

Compound of the invention 24 mg/canister Lecithin, NF Liq. Conc. 1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister.

The active compounds may be dosed as described depending on the inhalersystem used. In addition to the active compounds, the administrationforms may additionally contain excipients, such as, for example,propellants (e.g. Frigen in the case of metered aerosols),surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers (e.g. lactose in the case of powder inhalers) or, ifappropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g. Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inparticular in the case of powder inhalers, a number of technicalsolutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or theinhalers for example as described EP-A-0505321, which is incorporatedherein by reference in its entirety). Additionally, compounds of theinvention may be delivered in multi-chamber devices thus allowing fordelivery of combination agents.

Combinations.

Other compounds may be combined with compounds with which the inventionis concerned for the prevention and treatment of inflammatory diseases,in particular respiratory diseases. Thus, the present invention is alsoconcerned with pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of the present invention and one or moreother therapeutic agents. Suitable therapeutic agents for a combinationtherapy with compounds of the present invention include, but are notlimited to: (1) corticosteroids, such as fluticasone propionate,fluticasone furoate, mometasone furoate, beclometasone dipropionate,ciclesonide, budesonide, GSK 685698, GSK 870086, QAE 397, QMF 149, andTPI-1020; (2) β2-adrenoreceptor agonists such as salbutamol, albuterol,terbutaline, fenoterol, and long acting β2-adrenoreceptor agonists suchas salmeterol, indacaterol, formoterol (including formoterol fumarate),arformoterol, carmoterol, GSK 642444, GSK 159797, GSK 159802, GSK597501, GSK 678007, and AZD3199; (3) corticosteroid/long acting β32agonist combination products such as salmeterol/fluticasone propionate(Advair/Seretide), formoterol/budesonide (Symbicort),formoterol/fluticasone propionate (Flutiform), formoterol/ciclesonide,formoterol/mometasone furoate, formoterol/beclometasone dipropionate,indacaterol/mometasone furoate, Indacaterol/QAE 397, GSK 159797/GSK685698, GSK 159802/GSK 685698, GSK 642444/GSK 685698, GSK 159797/GSK870086, GSK 159802/GSK 870086, GSK 642444/GSK 870086, andarformoterol/ciclesonide; (4) anticholinergic agents, for examplemuscarinic-3 (M3) receptor antagonists such as ipratropium bromide,tiotropium bromide, Aclidinium (LAS-34273), NVA-237, GSK 233705,Darotropium, GSK 573719, GSK 961081, QAT 370, QAX 028, and EP-101; (5)dual pharmacology M3-anticholinergic/β2-adrenoreceptor agonists such asGSK961081, AZD2115, and LAS190792; (6) leukotriene modulators, forexample leukotriene antagonists such as montelukast, zafirulast orpranlukast or leukotriene biosynthesis inhibitors such as Zileuton orBAY-1005, or LTB4 antagonists such as Amelubant, or FLAP inhibitors suchas GSK 2190914, and AM-103; (7) phosphodiesterase-IV (PDE-IV) inhibitors(oral or inhaled), such as roflumilast, cilomilast, Oglemilast,ONO-6126, Tetomilast, Tofimilast, UK 500,001, and GSK 256066; (8)antihistamines, for example selective histamine-1 (H1) receptorantagonists, such as fexofenadine, citirizine, loratidine or astemizoleor dual H1/H3 receptor antagonists such as GSK 835726, GSK 1004723, orselective histamine-4 (H4) receptor antagonists, such as ZPL3893787; (9)antitussive agents, such as codeine or dextramorphan; (10) a mucolytic,for example N-acetyl cysteine or fudostein; (11) aexpectorant/mucokinetic modulator, for example ambroxol, hypertonicsolutions (e.g. saline or mannitol) or surfactant; (12) a peptidemucolytic, for example recombinant human deoxyribonoclease I(dornase-alfa and rhDNase) or helicidin; (13) antibiotics, for exampleazithromycin, tobramycin, and aztreonam; (14) non-selective COX-1/COX-2inhibitors, such as ibuprofen or ketoprofen; (15) COX-2 inhibitors, suchas celecoxib and rofecoxib; (16) VLA-4 antagonists, such as thosedescribed in WO 97/03094 and WO 97/02289, which are incorporated hereinby reference in their entireties; (17) TACE inhibitors and TNF-αinhibitors, for example anti-TNF monoclonal antibodies, such as Remicadeand CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;(18) inhibitors of matrix metalloprotease, for example MMP-12; (19)human neutrophil elastase inhibitors, such as ONO-6818 or thosedescribed in WO 2005/026124, WO 2003/053930, and WO 2006/082412, whichare incorporated herein by reference in their entireties; (20) A2bantagonists such as those described in WO 2002/42298, which isincorporated herein by reference in its entirety; (21) modulators ofchemokine receptor function, for example antagonists of CCR3 and CCR8;(22) compounds which modulate the action of other prostanoid receptors,for example a thromboxane A₂ antagonist; DP1 antagonists such asMK-0524, CRTH2 antagonists such as ODC9101 and OC000459 and AZD1981 andmixed DP1/CRTH2 antagonists such as AMG 009 and AMG853; (23) PPARagonists including PPAR alpha agonists (such as fenofibrate), PPAR deltaagonists, PPAR gamma agonists such as Pioglitazone, Rosiglitazone, andBalaglitazone; (24) methylxanthines such as theophylline oraminophylline and methylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate, andtheophylline/beclometasone dipropionate; (25) A2a agonists such as thosedescribed in EP 1 052 264 and EP 1 241 176, which are incorporatedherein by reference in their entireties; (26) CXCR2 or IL-8 antagonistssuch as SCH 527123 or GSK 656933; (27) IL-R signalling modulators suchas kineret and ACZ 885; (28) MCP-1 antagonists such as ABN-912.

The present invention is also directed to kits comprising thepharmaceutical compositions of compounds of the invention alone or incombination with or in admixture with one or more pharmaceuticallyacceptable carriers and/or excipients and a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler or anebulizer.

Methods of Synthesis.

In one aspect of the present invention, a process for the preparation ofcompounds of the invention is provided, according to general syntheticroutes described in this section. In the following reaction schemes,unless otherwise indicated, the groups mentioned assume the same meaningas those reported for compounds of formula (I).

The skilled person may introduce, where appropriate, suitable variationsto the conditions specifically described in the examples in order toadapt the synthetic routes to the provision of further compounds of theinvention. Such variations may include, but are not limited to, use ofappropriate starting materials to generate different compounds, changesin the solvent and temperature of reactions, replacement of reactantswith analogous chemical role, introduction or removal ofprotection/deprotection stages of functional groups sensitive toreaction conditions and reagents, as well as introduction or removal ofspecific synthetic steps oriented to further functionalization of thechemical scaffold.

Processes which can be used and are described and reported in Examplesand Schemes, should not be viewed as limiting the scope of the syntheticmethods available for the preparation of the compounds of the invention.

The process described is particularly advantageous as it is susceptibleof being properly modulated, through any proper variant known to theskilled person, so as to obtained any of the desired compounds of theinvention. Such variants are comprised within the scope of the presentinvention.

From all of the above, it should be clear to the skilled person that anyof the described groups may be present as such or in any properlyprotected form.

In particular, functional groups present in the intermediate andcompounds and which could generate unwanted side reaction andby-products, need to be properly protected before the alkylation,acylation, coupling or sulfonylation takes place. Likewise, subsequentdeprotection of those same protected groups may follow upon completionof the said reactions.

In the present invention, unless otherwise indicated, the term“protecting group” designates a protective group adapted to preserve thefunction of the group it is bound to. Typically, protective groups areused to preserve amino, hydroxyl, or carboxyl functions. Appropriateprotecting groups may thus include, for example, benzyl,benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like,which are well known to those skilled in the art (see, for a generalreference, T. W. Green; Protective Groups in Organic Synthesis (Wiley,N.Y. 1981), which is incorporated herein by reference in its entirety).

Likewise, selective protection and deprotection of any of the saidgroups, for instance including carbonyl, hydroxyl, or amino groups, maybe accomplished according to very well known methods commonly employedin organic synthetic chemistry.

Optional salification of the compounds of formula (I) or N-oxides on thepyridine ring thereof may be carried out by properly converting any ofthe free acidic or amino groups into the corresponding pharmaceuticallyacceptable salts. In this case too, the operative conditions beingemployed for the optional salification of the compounds of the inventionare all within the ordinary knowledge of the skilled person.

From all of the above, it should be clear that the above process,comprehensive of any variant thereof for the preparation of suitablecompounds of the invention, may be conveniently modified so that toadapt the reaction conditions to the specific needs, for instance bychoosing appropriate condensing agents, solvents and protective groups,as the case may be.

For example, compounds of the present invention of formula (I) may beprepared according to the route illustrated in Scheme 1:

Compounds of general formula (I) may be prepared from compounds ofgeneral formula (1b) by reaction with a compound of general formula(1c1) or (1c2) in a suitable solvent such as dimethyl sulfoxide,1,4-dioxane, DMF, or acetonitrile, in the presence of a base such asdiisopropylethylamine or sodium hydroxide at a range of temperatures,preferably between room temperature and 100° C.

Compounds of general formula (1c1) and (1c2) are either known in theliterature or may be prepared from amines of general formula (1d)according to known literature procedures (e.g. WO 2006/009741, EP 1 609789, WO 2008/033999, which are incorporated herein by reference in theirentireties).

Alternatively, Compounds of general formula (1d) are either known in theliterature or may be synthesized by one skilled in the art by adaptingappropriate literature methods (e.g. WO 201/0077836, WO 2006/009741, WO2008/125014, J. Med. Chem., 2007, 50, 4016, Bulletin des SocietesChimiques Belges, 1987, 96, 675-709, Organic & Biomolecular Chemistry,2006, 4, 4158-4164, which are incorporated herein by reference in theirentireties).

Compounds of general formula (1da), i.e. compounds of formula (1d)wherein R² is a group of formula (IVb) and R¹⁷, R¹⁸, z¹, z², z³ and z⁴are as defined above can be prepared from compounds of formula (1e):

using a suitable reducing agent such as tin (II) chloride, iron, orhydrogen gas with a suitable catalyst such as palladium on carbon, in asuitable solvent such as methanol, ethanol, or acetic acid, at a rangeof temperatures, preferably between room temperature and 100° C.

Compounds of general formula (1e) are known in the literature or may beprepared by those skilled in the art using literature methods (e.g. WO2008/034008, WO 2011/0189167, WO 2010/068258, which are incorporatedherein by reference in their entireties).

Alternatively, compounds of general formula (1da) as above defined canbe prepared from compounds of formula (1f), wherein R¹⁷, R¹⁸, z¹, z², z³and z⁴ are as defined above and wherein PG is a suitable compatibleprotecting group known to those skilled in the art, such as benzyl,benzyl carbamate or tert-butyl carbamate:

using suitable deprotection conditions such as hydrochloric acid,trifluoroacetic acid, or hydrogen catalysed by for example palladium oncarbon, in a suitable solvent such as dichloromethane, methanol, ethanolor acetic acid, at a range of temperatures, preferably between 0° C. and100° C.

Compounds of general formula (1f) can be prepared by reaction ofcompounds of formula (1g) shown below, wherein R¹⁷, R¹⁸, z¹, z², z³ andz⁴ are as defined above

with compounds of formula (1h) as shown above wherein PG is a suitableprotecting group known to those skilled in the art, such as benzyl,benzyl carbamate, or tert-butyl carbamate, using suitable conditionssuch as in the presence of a base such as potassium carbonate ordiisopropylethyl amine or under Buchwald conditions (with a catalystsuch as Pd(OAc)₂, a ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and base such as sodiumtert-butoxide), in a suitable solvent such as toluene ortetrahydrofuran, at a range of temperatures, preferably between roomtemperature and 150° C.

Compounds of general formula (1g) and (1h) are known in the literatureor may be prepared by those skilled in the art by adapting appropriateliterature methods (e.g. WO 2011/042389, Chemistry-A European Journal,2011, 17, 6606-6609, S6606/1-S6606/38, which are incorporated herein byreference in their entireties).

Compounds of general formula (Ib), may be prepared according to theroute illustrated in Scheme 2.

Compounds of general formula (1b) may be prepared from compounds ofgeneral formula (2a) by reaction with a compound of general formula(2b), (2c) or (2d), wherein G is a suitable chemical group known tothose skilled in the art selected such that it can facilitate a suitablecoupling reaction such as nucleophilic displacement or metal catalysedcross coupling. For example, in cases such that when Y is —O—, —S— or—NR⁷—, examples of G may include halogen or a suitable leaving groupsuch as mesylate or triflate either directly linked or attached via agroup —(CR³R⁴)_(n)—. Examples of the coupling conditions used mayinclude using a base such as sodium hydride or potassium tert-butoxideand 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitablesolvent such as N,N-dimethylformamide, toluene, 1,4-dioxane oracetonitrile at a range of temperatures, preferably between roomtemperature and 150° C. For example, in cases such that when Y is —O—and G is —OH or —SH, a method to perform this coupling may involveMitsunobu conditions (diethylazodicarboxylate/triphenylphosphine) in asuitable solvent such as tetrahydrofuran or 1,4-dioxane at a range oftemperatures preferably between −10° C. and 100° C. For example, incases such as when Y is —O—, —S— or —NR⁷— and G is a group such ashalogen, triflate or boronic acid/ester, a method to perform thiscoupling may be under metal (for example palladium or copper) catalyzedcoupling conditions in the presence of a suitable ligand such asXantphos or 1,10-phenanthroline in the presence of a base such ascaesium carbonate in a suitable solvent such as tetrahydrofuran,1,4-dioxane, or N,N-dimethylformamide at a range of temperaturespreferably between −10° C. and 150° C. For example, in cases such aswhen Y is —O— and G is a group such as —COOMe, —COOH, isocyanate, —OCOClor —NHCOOCH₂CCl₃, examples of conditions to perform this coupling mayinvolve the use of a base such as sodium hydride or triethylamine or acoupling reagent such as HATU in a suitable solvent such asdichloromethane, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamideat a range of temperatures preferably between −10° C. and 150° C.

Compounds of formula (2b) are known in the literature or may be preparedby those skilled in the art by adapting appropriate literature methods(e.g. WO 2006,133006, which is incorporated herein by reference in itsentirety).

Compounds of formula (2c) may be prepared according to the route inScheme 3:

Compounds of general formula (2c) may be prepared from compounds ofgeneral formula (3e) as shown above using a suitable oxidant such aschloramine T, lead tetracetate or phenyliodine(III) diacetate, in asuitable solvent such as dichloromethane or ethanol at a range oftemperatures, preferably between room temperature and 100° C.

Compounds of general formula (3e) may be prepared from compounds ofgeneral formula (3a) by reaction with an aldehyde of general formula(3c) in a suitable solvent such as ethanol or tetrahydrofuran at a rangeof temperatures, preferably between room temperature and 80° C.

Compounds of formula (3a) and (3c) are known in the literature or may beprepared by literature methods by those skilled in the art.

Alternatively, compounds of formula (2c) may be prepared from compoundsof formula (3d) using a suitable dehydrating agent such as Burgess'reagent, triphenyl phosphine and hexachloroethane, phosphorusoxychloride, acetic acid or Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in theabsence or presence of a suitable solvent such as tetrahydrofuran,toluene, or NMP, at a range of temperatures, preferably between roomtemperature and 120° C.

Compounds of formula (3d) may be prepared from compounds of formula (3a)by reaction with a compound of general formula (3b1) using a suitableacylating/dehydrating agent such astriphenylphosphine/trichloroacetonitrile/HOBt/2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide inthe presence of a base such as diisopropylethylamine, in a suitablesolvent such as dichloromethane or acetonitrile, at a range oftemperatures, preferably between room temperature and 150° C.

Alternatively, compounds of formula (3d) may be prepared from compoundsof formula (3a) by reaction with a compound of general formula (3b2) inthe presence of a base such as diisopropylethylamine, in a suitablesolvent such as dichloromethane or THF at a range of temperaturespreferably between −10° C. and the boiling point of the solvent.

Compounds of formulae (3b1) and (3b2) are known in the literature or maybe prepared by adapting appropriate literature methods by those skilledin the art.

Compounds of formula (2d) may be prepared according to the route inScheme 4:

Compounds of general formula (2d) may be prepared from compounds ofgeneral formula (4e) using a suitable oxidant such as chloramine T, leadtetracetate, or phenyliodine(III) diacetate, in a suitable solvent suchas dichloromethane or ethanol at a range of temperatures, preferablybetween room temperature and 100° C.

Compounds of general formula (4e) may be prepared from compounds ofgeneral formula (4a) by reaction with an aldehyde of general formula(4c) in a suitable solvent such as ethanol or tetrahydrofuran at a rangeof temperatures, preferably between room temperature and 80° C.

Compounds of formula (4a) and (4c) are known in the literature or may beprepared by literature methods by those skilled in the art.

Alternatively, compounds of formula (2d) may be prepared from compoundsof formula (4d) using a suitable dehydrating agent such as Burgess'reagent, triphenyl phosphine and hexachloroethane, phosphorusoxychloride, acetic acid or Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in theabsence or presence of a suitable solvent such as tetrahydrofuran,toluene, or NMP, at a range of temperatures, preferably between roomtemperature and 120° C.

Compounds of formula (4d) may be prepared from compounds of formula (4a)by reaction with a compound of general formula (4b1) using a suitableacylating/dehydrating agent such astriphenylphosphine/trichloroacetonitrile/HOBt/2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide inthe presence of a base such as diisopropylethylamine, in a suitablesolvent such as dichloromethane or acetonitrile, at a range oftemperatures, preferably between room temperature and 150° C.

Alternatively, compounds of formula (4d) may be prepared from compoundsof formula (4a) by reaction with a compound of general formula (4b2) inthe presence of a base such as diisopropylethylamine, in a suitablesolvent such as dichloromethane or THF at a range of temperaturespreferably between −10° C. and the boiling point of the solvent.

Compounds of formulae (4b1) and (4b2) are known in the literature or maybe prepared by adapting appropriate literature methods by those skilledin the art.

Alternatively, compounds of formula (2c) may be prepared according tothe route in Scheme 5:

Compounds of general formula (2c) may be prepared by reaction ofcompounds of general formula (5b) wherein, G² is a group such as ahalogen, with compounds of general formula (5c) wherein G³ is a groupsuch as a halogen, boronic acid, boronic ester, or organo stannane,using a cross-coupling method such as that using a suitable catalystsuch as tetrakis(triphenylphosphine)palladium (0) or palladium (II)acetate, in the presence of a base such as caesium carbonate or sodiumtert-butoxide, in a suitable solvent such as toluene or DMF at a rangeof temperatures, preferably between room temperature and 150° C.

Compounds of formula (5b) can be prepared from compounds of generalformula (5a) using for example a suitable halogenating agent such asN-bromosuccinimide or N-iodosuccinimide, in a solvent such as DMF ortetrahydrofuran at a range of temperatures, preferably between roomtemperature and 100° C.

Compounds of formula (5a) may be prepared from compounds of generalformula (3a) using a reagent such as triethylorthoformate, in absence orthe presence of a solvent such as, ethanol, under neutral, basic oracidic conditions at a range of temperatures preferably room temperatureto 100° C. Compounds of formula (3a) can be prepared as described above.

It will be appreciated that the methods described in Scheme 5 can beadapted by those skilled in the art to provide compounds of formula (2d)using compounds of formula (4a).

Compounds of general formula (2aa), i.e. compounds of formula (2a)wherein Y═O and W═NH may be prepared according to the route illustratedin scheme 6:

For example, compounds of general formula (2aa) may be prepared asdescribed in WO 2008/043019, which is incorporated herein by referencein its entirety. Compounds of general formula (2aa) may be prepared fromcompounds of general formula (6a1) or (6a2) wherein PG is a suitableprotecting group (such as trifluoroacetate or tert-butyl carbamate)known to those skilled in the art using suitable deprotection conditionssuch as sodium hydroxide in methanol and water or trifluoroacetic acidin dichloromethane.

Compounds of general formulae (6a1) and (6a2) may be prepared fromcompounds of general formula (6b).

Compounds of general formula (6a1), wherein PG is an amide, preferablytrifluoroacetamide, may be prepared from compounds of general formula(6b) as described in WO 2008/043019, which is incorporated herein byreference in its entirety, using RuCl[S,S-Tsdpen(p-cymene)].

Compounds of general formula (6a2), wherein PG is an amide, preferablytrifluoroacetamide, may be prepared from compounds of general formula(6b) as described in WO 2008/043019, which is incorporated herein byreference in its entirety, using RuCl[R,R-Tsdpen(p-cymene)]. It will berecognised that compounds of formula (6b) may be homochiral asillustrated or be the opposite enantiomer or racemic.

It will be realized by those skilled in the art that any combination ofstereocentres in (2a) can be prepared using both enantiomers of (6b) andusing RuCl[R,R-Tsdpen(p-cymene)] or RuCl[S,S-Tsdpen(p-cymene)]. Compound(2aa) is drawn with no defined stereocenters but any combination thereofcan be obtained as illustrated in Scheme 2.

Compounds of formula (6b) can be prepared from compounds of formula (6c)

using a suitable oxidant such as potassium permanganate and magnesiumsulfate in a suitable solvent methanol/water at a range of temperaturespreferably between room temperature and the boiling point of thesolvent. It will be recognized that compounds of formula (6c) may behomochiral as illustrated or be the opposite enantiomer or racemic.

Compounds of formula (6c) can be prepared from compounds of formula (6d)where PG is a suitable protecting group such as trifluoroacetate ortert-butyl carbonate:

using ethyl trifluoroacetate or di-tert-butyl dicarbonate in thepresence of base such as triethylamine or diisopropylethylamine in asolvent such as methanol or dichloromethane at a range of temperaturespreferably between 0° C. and the boiling point of the solvent. It willbe recognized that compounds of formula (6d) may be homochiral asillustrated or be the opposite enantiomer or racemic.

Compounds of formula (6d) are known in the literature and may beprepared by those skilled in the art by adapting literature methods(e.g. for S-(+)-1-amino-1,2,3,4-tetrahydronaphthalene, see Journal ofthe Chemical Society, Perkin Transactions 1: 1985, 2039-44; for(S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline, see Journal of OrganicChemistry, 2007, 72, 669-671; and for 1-aminoindan, see TetrahedronLetters, 2011, 52, 1310-1312, which are incorporated herein by referencein their entireties)

Compounds of formula (Ib), i.e. compounds of formula (1) where Y═NR⁷ andW═NH and A, R¹, R², and R⁷ are as defined above, may be prepared,according to the route illustrated in Scheme 7.

Compounds of general formula (Ib) as above defined may be prepared fromcompounds of general formula (7b), where Y═NR⁷ and W═NH by reaction witha compound of general formula (1c1) in a suitable solvent such asdimethyl sulfoxide, 1,4-dioxane, DMF or acetonitrile, in the presence ofa base such as diisopropylethylamine or sodium hydroxide at a range oftemperatures, preferably between 0° C. and 100° C.

Compounds of general formula (7b) may be prepared from compounds ofgeneral formula (7a), where Y═NR⁷ and W═NH and wherein PG is a suitableprotecting group such as trifluoroacetamide, tert-butyl carbamate orbenzyl carbamate using suitable deprotection conditions such as, sodiumhydroxide in methanol, trifluoroacetic acid in dichloromethane orhydrogen catalysed by for example palladium on carbon in ethanol, at arange of temperatures, preferably between 0° C. and 100° C.

Compounds of general formula (7a), may be prepared from compounds ofgeneral formula (7d) and (6b) using a suitable reducing agent such assodium triacetoxyborohydride or sodium borohydride in a suitable solventsuch as 1,2-dichloroethane, methanol or acetic acid, at a range oftemperatures, preferably between 0° C. and 100° C.

Alternatively, compounds of general formula (7a), may be prepared fromcompounds of general formulae (7d) and (7g), wherein PG is a suitableprotecting group known to those skilled in the art, such astrifluoroacetamide, tert-butyl carbamate and benzyl carbamate and G⁶ isa suitable chemical group known to those skilled in the art selectedsuch that it can facilitate a reaction such as a nucleophilicdisplacement, for example a halogen or an oxygen atom which has asuitable substituent such as mesylate or triflate, by using a suitablebase such as diisopropylethylamine or potassium carbonate in a suitablesolvent such as DMF, tetrahydrofuran or acetonitrile at a range oftemperatures, preferably between 0° C. and 100° C.

Compounds of formula (7g) can be prepared from compounds of formula (6a)using conditions such as carbon tetrabromide and triphenylphosphine ormethanesulfonyl chloride and diisopropylethylamine, in a suitablesolvent such as dichloromethane or acetonitrile at a range oftemperatures, preferably between 0° C. and 100° C.

Alternatively, compounds of formula (7a) may be prepared from compoundsof general formula (7h) by reaction with (2b), (2c) and (2d), in theoptional presence of a catalyst such as copper (I) iodide ortris(dibenzylideneacetone)dipalladium(0), in the optional presence of aligand such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, using a basesuch as diisopropylethyl amine, sodium tert-butoxide or sodium hydridein a solvent such as DMF, toluene or tetrahydrofuran at a range oftemperatures preferably between room temperature and 150° C.

Compounds of formula (7h) can be prepared from compounds of formula (7k)by reaction with compounds of formula (6b); wherein PG is a suitableprotecting group known to those skilled in the art, such astrifluoroacetamide, tert-butyl carbamate and benzyl carbamate, by usinga suitable reducing agent such as sodium triacetoxyborohydride or sodiumborohydride in a suitable solvent such as 1,2-dichloroethane, methanolor acetic acid, at a range of temperatures, preferably between 0° C. and100° C.

Alternatively, compounds of formula (7h) can be prepared from compoundsof formula (7k) using compounds of formula (7g); wherein PG is asuitable protecting group known to those skilled in the art, such astrifluoroacetamide, tert-butyl carbamate and benzyl carbamate and G⁶ isa suitable chemical group known to those skilled in the art selectedsuch that it can facilitate a nucleophilic displacement reaction, suchas a halogen or an oxygen atom which has a suitable substituent such asmesylate or triflate, by using a suitable base such asdiisopropylethylamine or potassium carbonate in a suitable solvent suchas DMF, tetrahydrofuran or acetonitrile at a range of temperatures,preferably between 0° C. and 100° C.

Compounds of general formula (7d), may be prepared from compounds ofgeneral formula (7e) and (7f) wherein G⁴ is a suitable chemical groupknown to those skilled in the art selected such that it can facilitate anucleophilic displacement reaction, such as a halogen or an oxygen atomwhich has a suitable substituent such as mesylate or triflate, by usinga suitable base such as diisopropylethylamine or potassium carbonate ina suitable solvent such as DMF, tetrahydrofuran or acetonitrile at arange of temperatures, preferably between 0° C. and 100° C.

Compounds of formula (7e) and (7f) are known in the literature or may beprepared by those skilled in the art using literature procedures (e.g.Organic Letters, 2002, 4, 3423-3426, which is incorporated herein byreference in its entirety).

Compounds of formula (1ba), i.e. compounds of formula (1b) whereY═(CR⁵R⁶)_(n) and W═NH, may be prepared according to the routeillustrated in Scheme 8.

Compounds of formula (1ba) may be prepared from compounds of formula(8c) wherein PG is a suitable protecting group known to those skilled inthe art, such as trifluoroacetamide, tert-butyl carbamate and benzylcarbamate by using suitable deprotection conditions such as, sodiumhydroxide in methanol, trifluoroacetic acid in dichloromethane orhydrogen gas catalysed by for example palladium on carbon in ethanol, ata range of temperatures, preferably between 0° C. and 100° C.

Compounds of formula (8c) may be prepared from compounds of formula (8b)wherein PG is a suitable protecting group known to those skilled in theart, such as trifluoroacetamide, tert-butyl carbamate, and benzylcarbamate by using hydrogen gas in the presence of a catalyst such aspalladium on carbon, in a suitable solvent such as methanol or ethanol,in the presence or absence of an acid such as HCl, at a range oftemperatures, preferably between 0° C. and 100° C.

Compounds of formula (8b) may be prepared from compounds of formula (8a)and (8f) by a reaction such as a cross-coupling using a suitablecatalyst such as tetrakis(triphenylphosphine)palladium (0) or palladiumacetate, and a base such as diisopropylethylamine, sodium tert-butoxideor caesium carbonate in a suitable solvent such as NMP, toluene, or DMF,at a range of temperatures, preferably between 0° C. and 100° C.Alternatively (8b) may be prepared by adapting literature procedures(e.g. those reported in WO 2009/022633, which is incorporated herein byreference in its entirety).

Compounds of formula (8f) are known in the literature or may be preparedby those skilled in the art by adapting literature procedures (e.g. WO2008/063287, which is incorporated herein by reference in its entirety).

Compounds of formula (8a) may be prepared from compounds of formula (6b)using a triflating agent such as triflic anhydride, in the presence of asuitable base such as pyridine or 2,6-bis(tert-butyl)-4-methylpyridine,in a solvent such as dichloromethane or chloroform at a range oftemperatures, preferably between 0° C. and boiling point of the solvent.Alternatively (8a) may be prepared by adapting literature procedures(e.g. those described in WO 2009/022633, which is incorporated herein byreference in its entirety).

Compounds of the invention of formula (Id), i.e. compound of formula (1)where Y═O and W═O and R¹, R² and A are as defined above, may beprepared, according to the route illustrated in Scheme 9.

Compounds of general formula (Id) may be prepared from compounds ofgeneral formula (9b) where Y═O and W═O and (9d) wherein G⁷ is a suitablechemical group such as a halogen or alkoxy, using a suitable base suchas diisopropylethylamine, potassium carbonate, or sodium hydride in asuitable solvent such as DMF, tetrahydrofuran, or acetonitrile at arange of temperatures, preferably between 0° C. and 100° C.

Compound of formula (9b) can be prepared from compounds of formula (9a)and (2b), (2c), or (2d). Compounds of formula (9a) are known in theliterature and can be prepared by those skilled in the art by adaptingliterature methods (e.g. Angewandte Chemie, International Edition, 2006,45, 98-101 and Chimia, 2007, 61, 169-171, which are incorporated hereinby reference in their entireties).

Compounds of formula (9d) are known in the literature and can beprepared by those skilled in the art using literature methods.Alternatively, compounds of formula (9d) can be prepared from compoundsof formula (1d) using alkyl chloroformate, dialkyl anhydride or phosgenein the optional presence of a base such as sodium hydroxide ordiisopropylethylamine in a solvent such as dichloromethane, dioxane, ortetrahydrofuran at a range of temperatures preferably between 0° C. andthe boiling point of the solvent.

Compounds of the invention of formula (Ie), i.e. compounds of formula(I) wherein Y═S and W═NH, may be prepared according to the routeillustrated in scheme 10:

Compounds of general formula (Ie) may be prepared from compounds ofgeneral formula (10h), wherein Y═S and W═NH: using compounds of formula(1c1) or (1c2) in a suitable solvent such as dimethyl sulfoxide,1,4-dioxane, N,N-dimethylformamide, or acetonitrile, in the presence ofa base such as diisopropylethylamine at a range of temperatures,preferably between room temperature and 100° C.

Compounds of formula (10h) wherein Y═S and W═NH may be prepared fromcompounds of formula (10g) using deprotection conditions such ashydrazine in methanol at a range of temperatures preferably between roomtemperature and the boiling point of the solvent.

Compounds of formula (10g) wherein Y═S, can be prepared from compoundsof formula (100f) by reaction with compounds of formulae (2b), (2c) or(2d). Examples of the coupling conditions used may include using a basesuch as sodium hydride or potassium tert-butoxide and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitable solventsuch as N,N-dimethylformamide, toluene, 1,4-dioxane, or acetonitrile ata range of temperatures, preferably between room temperature and 150° C.Alternative methods to perform this coupling may involve Mitsunobuconditions (diethylazodicarboxylate/triphenylphosphine) or metal (forexample palladium) catalysed coupling conditions in a suitable solventsuch as tetrahydrofuran or 1,4-dioxane at a range of temperaturespreferably between −10° C. and 150° C.

Compounds of formula (10f) can be prepared from compounds of formula(10e) using dithiothreitol, monopotassium phosphate, potassium carbonatein a solvent such as methanol in the presence of acetic acid at a rangeof temperatures preferably between room temperature and the boilingpoint of the solvent.

Compounds of formula (10e) can be prepared from compounds of formula(10d) using 2-nitrobenzenesulfenyl chloride in acetic acid at a range oftemperatures preferably between room temperature and 100° C.

Compounds of formula (10d) can be prepared from compounds of formula(100c) using phthalimide, triphenylphosphine, and diisopropylazodicarboxylate in a solvent such as tetrahydrofuran at a range oftemperature preferably between 0° C. and the boiling point of thesolvent.

Compounds of formula (10c) can be prepared from compounds of formula(10b) using a reducing agent such as sodium borohydride in a solventsuch as methanol at a range of temperatures preferably between 0° C. andthe boiling point of the solvent.

Compounds of formula (10b) can be prepared from compounds of formula(10a) using tert-butanethiol in the presence of a base such asdiisopropylethyl amine in a solvent such as tetrahydrofuran at a rangeof temperatures preferably between 0° C. and the boiling point of thesolvent.

Compounds of formula (10a) are known in the literature and can beprepared by those skilled in the art using literature methods (e.g.3-bromo-indan-1-one, see WO 2010/108058, which is incorporated herein byreference in its entirety)

Alternatively, compounds of general formula (1bb), i.e. compounds offormula (1b) wherein Y═CH₂ and W═NH may be prepared according to theroute illustrated in scheme 11:

Compounds of general formula (1bb) may be prepared from compounds ofgeneral formula (11b) by removal of the protecting group PG usingmethods known in the art such as aqueous sodium hydroxide in a solventsuch as methanol at a range of temperatures preferably between roomtemperature and 100° C.

Compounds of formula (11b) may be prepared from compounds of generalformula (11a) by reaction with a suitable reduction agent for examplehydrogen gas in the presence of a suitable catalyst such as palladium onactivated charcoal in a suitable solvent such as ethanol at a range oftemperatures between room temperature and 70° C. and pressures betweenatmospheric and 4 Barr.

Compounds of formula (11a) may be prepared from compounds of generalformula (6a) by means of a reaction such as a Wittig (or one of theclosely related variants such as the Horner-Wadsworth-Emmons) with asuitable substrate such as R¹—CH₂—P(O)(OMe)₂ in the presence of asuitable base such as sodium hydride in a suitable solvent such astetrahydrofuran at a range of temperatures preferably between −10° C.and 100° C.

Compounds such as R¹—CH₂—P(O)(OMe)₂ may be synthesised from compounds ofthe general formula R¹—CH₂-Hal wherein Hal represents a halogen such as—Br or —Cl by reaction with a compound such as trimethylphosphite at arange of temperatures preferably between 0° C. and 100° C.

Compounds such as R¹—CH₂-Hal may be synthesised from compounds offormula R¹—CH₃ by means of a reaction such as a radical halogenationusing a reagent such as N-bromosuccinimide in the presence of a catalystsuch as AIBN in a suitable solvent such as carbon tetrachloride at arange of temperatures preferably between 0° C. and 80° C. Compounds suchas R¹—CH₂-Hal may also be synthesised from compounds formula R¹—CH₂—OHby means of using halogenating conditions such as carbon tetrabromideand triphenylphosphine in dichloromethane or activation conditions suchas methane sulfonyl chloride in dichloromethane in the presence of basesuch as diisopropylamine.

Compounds such as R¹—CH₃ and R¹—CH₂—OH may be prepared by methodsoutlined above for compounds (2b), (2c) and (2d).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES General Experimental Details

Abbreviations used in the experimental section:

AcOH=acetic acid;

aq.=aqueous;

DCM=dichloromethane;

DIAD=Diisopropyl azodicarboxylate;

DIPEA=diisopropylethylamine;

DMAP=N,N-dimethylaminopyridine;

DMF=N,N-dimethylformamide;

DMSO=dimethyl sulfoxide;

EDC=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide Hydrochloride;

EtOAc=ethyl acetate;

EtOH=ethanol;

Et₂O=diethyl ether;

Et₃N=triethylamine;

EtNiPr₂=diisopropylethylamine;

FCC=flash column chromatography;

h=hour;

HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;

HOBt=1-hydroxy-benzotriazole; HPLC=high performance liquidchromatography;

IMS=Industrial Methylated Spirits;

LCMS=liquid chromatography mass spectrometry;

NaOH=sodium hydroxide;

MeCN=acetonitrile;

MeOH=MeOH;

min=minutes;

NH₃=ammonia;

NMR=nuclear magnetic resonance;

RT=room temperature;

Rt=retention time;

sat.=saturated;

SCX-2=strong cation exchange chromatography;

TFA=trifluoroacetic acid;

THF=Tetrahydrofuran;

H₂O=water;

IMS=industrial methylated spirit;

Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;

X-Select=Waters X-select HPLC column;

IPA=propan-2-ol;

LDA=lithium diisopropylamide;

MDAP=mass-directed auto-purification;

MeOH=methanol;

Ph₃P=triphenylphosphine;

TBAF=tetrabutylammonium fluoride.

In the procedures that follow, after each starting material, referenceto a Intermediate/Example number is usually provided. This is providedmerely for assistance to the skilled chemist. The starting material maynot necessarily have been prepared from the batch referred to.

When reference is made to the use of a “similar” or “analogous”procedure, as will be appreciated by those skilled in the art, such aprocedure may involve minor variations, for example reactiontemperature, reagent/solvent amount, reaction time, work-up conditionsor chromatographic purification conditions.

The nomenclature of structures was assigned using Autonom 2000 Namesoftware from MDL Inc. When the nomenclature of structures could not beassigned using Autonom, ACD/Name software utility part of the ACD/LabsRelease 12.00 Product Version 12.5 (Build 45133, 16 Dec. 2010) was used.Stereochemical assignments of compounds are based on comparisons withdata reported in WO 2008/043019, which is incorporated herein byreference in its entirety, for key intermediates. All reactions werecarried out under anhydrous conditions and an atmosphere of nitrogen orargon unless specified otherwise. Unless otherwise stated alltransformations were carried at ambient temperature (room temperature).

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer witha 5 mm inverse detection triple resonance probe operating at 400 MHz oron a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detectiontriple resonance TXI probe operating at 400 MHz or on a Bruker AvanceDPX 300 spectrometer with a standard 5 mm dual frequency probe operatingat 300 MHz. Shifts are given in ppm relative to tetramethylsilane (δ=0ppm). J values are given in Hz through-out. NMR spectra were assignedusing DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version 3.

Where products were purified by flash column chromatography, ‘flashsilica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure ofnitrogen up to 10 p.s.i accelerated column elution or use of theCombiFlash® Companion purification system or use of the Biotage SP1purification system. All solvents and commercial reagents were used asreceived.

Compounds purified by preparative HPLC were purified using aC18-reverse-phase column (100×22.5 mm i.d Genesis column with 7 μmparticle size), or a Phenyl-Hexyl column (250×21.2 mm i.d. Gemini columnwith 5 μm particle size), UV detection between 220-254 nm, flow 5-20mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile(containing 0.1% TFA or 0.1% formic acid) or water/MeOH (containing 0.1%TFA or 0.1% formic acid), or a C18-reverse-phase column (19×250 mm,XBridge OBD, with 5 μm particle size), eluting with gradients from 100-0to 0-100% water/acetonitrile (containing 0.1% NH₄OH); or a ChiralPak ICcolumn (10×250 mm i.d., with 5 μm particle size), unless otherwiseindicated. Fractions containing the required product (identified by LCMSanalysis) were pooled, the organic solvent removed by evaporation, andthe remaining aqueous residue lyophilised, to give the final product.Products purified by preparative HPLC were isolated as free base,formate or TFA salts, unless otherwise stated.

The Liquid Chromatography Mass Spectroscopy (LCMS) and HPLC systems usedare:

Method 1.

Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-phasecolumn (30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μL split to MS with in-line HP1100 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 2.

Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μL split to MS with in-line Waters 996 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 3.

Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μL split to MS with in-line HP1100 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 4.

VG Platform II quadrupole spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size, elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.05 95 5.30 2.0 5 95 5.80 2.0 95 5 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μl/min split to the ESI source with inlineHP1050 DAD detector). MS ionization method—Electrospray (positive andnegative ion).

Method 5.

Waters micromass ZQ2000 quadrupole mass spectrometer with an Acquity BEHC18 1.7 um 100×2.1 mm, Acquity BEH Shield RP18 1.7 um 100×2.1 mm orAcquity HSST3 1.8 um 100×2.1 mm, maintained at 40° C. Elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.45 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Detection—MS, UV PDA. MS ionization method—Electrospray (positive andnegative ion).

Method 6.

Phenomenex Gemini C18-reverse-phase column (250×21.20 mm 5 μm particlesize), elution with A: water+0.1% formic acid; B: CH₃CN+0.1% formicacid. Gradient—90% A/10% B to 2% A/98% B over 20 min−flow rate 18mL/min. Detection—In-line UV detector set at 254 nM wavelength.

Method 7.

Agilent 1260 inifinity purification system. Column: XSELECT CSH Prep C18OBD, partical size 5 μm, 30×150 mm, RT. Elution with A: water+0.1%formic acid; B: CH₃CN+0.1% formic acid. Gradient—90% A/10% B to 2% A/95%B over 22 min−flow rate 60 mL/min. Detection—In-line Agilent 6100 seriessingle Quadrupole LC/MS.

It is to be understood by the skilled person that, where the expression“partial formate salt” is used, it is to be intended as identifyingderivatives where only part of the basic compound has been convertedinto formate salt and thus containing less than one equivalent offormate counterion. Exact salt/free base ratio is provided by associatedNMS analysis.

Example 11-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 2,2,2-Trifluoro-N—(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-acetamide(Intermediate 1a)

Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to asolution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar;25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL)at RT and stirred for 18 h. The mixture was concentrated toapproximately ⅓ of its volume and then partitioned between DCM (200 mL)and water (200 mL). The aqueous layer was extracted into DCM (3×) andthe combined organic layers were washed with brine, dried (MgSO₄) andconcentrated in vacuo to yield the title compound (41.1 g, 169 mmol,99%). ¹H NMR (400 MHz, CDCl₃): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m),2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J=5.0 Hz), 6.38-6.48 (1H, br s),7.12-7.16 (1H, m), 7.20-7.26 (3H, m).

b.2,2,2-Trifluoro-N—((S)-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(Intermediate 1b)

Magnesium sulfate monohydrate (46.6 g, 338 mmol) in water (500 mL) wasadded to an ice cold solution of Intermediate 1a (41.1 g, 169 mmol) inacetone (1.0 L). Potassium permanganate (80.1 g, 507 mmol) was addedportionwise (10.0 g portions) over a period of 45 min. The mixture wasthen stirred for 18 h. Sodium thiosulfate pentahydrate (126 g, 510 mmol)in water (400 mL) was added, and the reaction stirred for min. Themixture was concentrated to ˜300 mL, then water (1.0 L), Celite (60g)and EtOAc (1.0 L) were sequentially added. The mixture was thoroughlystirred, and then filtered through a pad of Celite. The aqueous layerwas extracted into EtOAc (3×) and the combined organic layers washedwith brine, dried (MgSO₄) and concentrated in vacuo to yield the titlecompound (36.6 g, 142 mmol, 84%). ¹H NMR (400 MHz, CDCl₃): 2.20-2.30(1H, dddd, J 13.3, 10.0, 8.8, 4.5 Hz), 2.43-2.52 (1H, dddd, J 13.3, 7.2,4.6, 4.6 Hz), 2.67-2.77 (1H, ddd, J 17.4, 10.1, 4.6 Hz), 2.78-2.88 (1H,ddd, J 17.4, 7.1, 4.6 Hz), 5.39-5.47 (1H, td, 8.5, 4.5 Hz), 7.32-7.37(1H, d, J=7.7 Hz), 7.44-7.49 (1H, t, J=7.6 Hz), 7.59-7.64 (1H, td, J7.6, 1.4 Hz), 8.03-8.07 (1H, dd, J 7.7, 1.4 Hz).

c.2,2,2-Trifluoro-N-((1S,4R)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(Intermediate 1c)

Degassed DMF (argon sparged, 100 mL) was added to Intermediate 1b (8.00g, 31.3 mmol) and[N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium(Strem Chemicals Inc.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6mmol) was added slowly to ice cold formic acid (2.34 mL, 62.6 mmol) andstirred for 20 min; this was then added to the DMF solution. Thereaction was heated to 60° C. for 18 h. After cooling, the mixture waspartitioned between DCM (200 mL) and water (600 mL). The aqueous layerwas extracted DCM (3×) and the combined organic layers washed withbrine, dried (MgSO₄) and concentrated in vacuo. Purification by FCC,using 0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g,27.4 mmol, 88%). ¹H NMR (400 MHz, CDCl₃): 1.88-1.92 (1H, d, J=4.8 Hz),1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H,br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).

d. (1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol (Intermediate 1d)

Sodium hydroxide (2.10 g, 53.0 mmol) was added to an ice cold solutionof Intermediate 1c (3.43 g, 13.2 mmol) in MeOH/water (2:1, 50 mL) andstirred for 3.5 h. The mixture was loaded on to a SCX-2 cartridge,eluting with MeOH then 2M NH₃ in MeOH, to yield the title compound (2.30g, 13.2 mmol, 99%). ¹H NMR (400 MHz, d₆-DMSO): 1.66-1.90 (4H, m),3.71-3.77 (1H, t, J=5.4 Hz), 4.46-4.54 (1H, t, J=5.4 Hz), 7.14-7.22 (2H,m), 7.32-7.38 (1H, m), 7.40-7.46 (1H, m).

e. Isobutyric acid N′-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate1e)

To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference proceduresee WO 2010/022076, which is incorporated herein by reference in itsentirety; 2.08 g, 16.4 mmol), isobutyric acid (1.82 mL, 19.6 mmol), andHOBt hydrate (251 mg, 1.64 mmol) in DCM (50 mL), EDC (3.76 g, 19.6 mmol)was added, and the resulting orange solution was stirred at roomtemperature for 18 h. Sat. aq. NaHCO₃ (50 mL) was added, and the mixturewas stirred vigorously for 15 min. The organics were washed with sat.aq. NaHCO₃ (50 mL), passed through a hydrophobic frit, and concentratedunder vacuum to leave a pale brown solid. The solid was suspended inEt₂O (50 mL) and filtered, washing with Et₂O (25 mL), to leave a whitesolid (1.48 g, 46%). The ethereal washings were concentrated undervacuum and the residue suspended in Et₂O (10 mL), filtered, washed withEt₂O (2×2 mL), to leave a white solid (330 mg, 10%). The solids werecombined (1.81 g, 56%). ¹H NMR (400 MHz, CDCl₃): 1.23 (6H, d), 2.50 (1H,sept), 6.65 (1H, dd), 6.80 (1H, d), 7.29 (1H, ddd), 7.77 (1H, br s),8.01 (1H, d).

f. 6-Fluoro-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 1f)

To a solution of Intermediate 1e (1.81 g, 9.18 mmol), triphenylphosphine(4.83 g, 18.4 mmol), and triethylamine (5.12 mL, 36.7 mmol) in THF (25mL) at 0° C., hexachloroethane (4.36 g, 18.4 mmol) was added in 2portions at a 1 min intervals. The resulting pale brown solution wasallowed to warm to RT then stirred for 2 h. The resulting yellowsuspension was filtered, washing with THF (2×25 mL). The combinedorganics were purified using SCX-2 cartridge (washed with DCM-MeOH (1:1,100 mL) and MeOH (50 mL), and then the product was eluted with 2M NH₃ inMeOH) to give a pale yellow solid (1.60 g, 97%, contaminated with ˜2.5%Ph₃P═O). ¹H NMR (400 MHz, CDCl₃): 1.53 (6H, d), 3.32 (1H, sept), 7.15(1H, ddd), 7.75 (1H, ddd), 7.84 (1H, m).

g.(1S,4R)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-cis-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 1g)

Intermediate 1d (634 mg, 3.88 mmol) was added portionwise to asuspension of sodium hydride (60% in mineral oil, 466 mg, 11.65 mmol) indry DMF (5 mL), and the mixture stirred at RT for 20 min. Intermediateif (535 mg, 2.99 mmol) was then added portionwise, and the mixtureheated at 60° C. for 4 h. The reaction was cooled, quenched with water,and extracted with EtOAc (3×). The combined organic extracts were washedwith brine and dried (Na₂SO₄), evaporated and purified by SCX-2 elutingwith MeOH then 2M NH₃ in MeOH, to afford the title compound (274 mg,79%). LCMS (Method 1): Rt 1.76 min, m/z 180 [MH⁺].

h.1-(5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 1)

A solution of Intermediate 1g (87 mg, 0.27 mmol), DIPEA (318 μL, 1.86mmol) and [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloroethyl ester (for reference procedure see WO2001/004115, which is incorporated herein by reference in its entirety;260 mg, 0.62 mmol) in DMF (5 mL) was heated at 60° C. for 2 h. Aftercooling, the solution was passed through a SCX-2 cartridge, eluting withMeOH then 2M NH₃ in MeOH, to afford the crude title compound. Furtherpurification by HPLC (55-98% H₂O in MeCN (0.1% NH₃)) gave the titlecompound as a colourless powder (35 mg, 9.5%). LCMS (Method 5): Rt 4.46min, m/z 594 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.21 (9H, s), 1.31-1.35(6H, dd, J 5.8), 1.76-1.93 (3H, m), 2.01-2.08 (2H, m), 3.47-3.57 (1H,m), 3.75 (3H, s), 4.75-4.81 (1H, m), 5.48 (1H, t, J 3.9), 6.26 (1H, s),6.98-7.05 (3H, m), 7.09-7.13 (1H, m), 7.09-7.13 (6H, m), 7.62-7.65 (1H,d, J 9.98).

Example 21-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Diisopropylethylamine (54 μL, 0.31 mmol) was added to a solution ofIntermediate 1g (100 mg, 0.31 mmol) and(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (for reference procedure see US2004/192653,which is incorporated herein by reference in its entirety; 102 mg, 0.31mmol) in 1,4-dioxane (3.0 mL). The reaction was heated to 100° C. for 18h. After cooling, the mixture was partitioned between EtOAc (50 mL) andwater (50 mL). The aqueous layer was extracted into EtOAc (3×) and thecombined organic layers were washed with brine, dried (MgSO₄) andconcentrated in vacuo. Purification by FCC, using 0-10% [2M NH₃ in MeOH]in DCM, followed by HPLC (10-98% MeCN in H₂0, 0.1% formic acid) affordedthe title compound (63 mg, 0.13 mmol, 41%). LCMS (Method 5: Rt 3.71mins, m/z 502 [MH⁺]. ¹H NMR (400 MHz, CDCl₃): 1.24 (9H, s), 1.41-1.44(3H, d, J 6.9), 1.45-1.48 (3H, d, J 6.9), 1.90-2.00 (1H, m), 2.04-2.17(2H, m), 2.22-2.30 (1H, m), 3.18-3.29 (1H, sp, J 6.9), 3.72 (3H, s),5.08-5.15 (1H, td, J 8.8, 5.2), 5.16-5.21 (1H, t, J 3.8), 5.45-5.55 (1H,br d, J 7.4), 6.02 (1H, s), 6.60-6.68 (1H, br s), 6.99-7.04 (1H, dd, J9.9, 2.1), 7.24-7.28 (2H, m), 7.30-7.36 (1H, m), 7.36-7.44 (2H, m),7.56-7.60 (1H, d, J 9.9).

Example 31-{5-tert-Butyl-2-[3-(2-hydroxyethylsulfanyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. Di-tert-butyl1-{3-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)sulfanyl]phenyl}hydrazine-1,2-dicarboxylate(Intermediate 3a)

A mixture of 3-bromothiophenol (1.00 g, 5.29 mmol),bromoethoxydimethylsilyl ether (1.36 mL, 6.35 mmol) and potassiumcarbonate (1.46 g, 10.58 mmol) in acetone (15 mL) was stirred at RTovernight. The mixture was filtered, evaporated, the residue dried undervacuum, and then dissolved in dry THF (15 mL). nBuLi (1.6M in hexanes,4.5 mL, 7.28 mmol) was added dropwise at −78° C. and stirred for 10 min.Di-tert-butyl azodicarboxylate (1.54 g, 6.68 mmol) was added in oneportion at −78° C. and stirred for min. The mixture was then allowed towarm to RT over 2 h. The mixture was partitioned between saturatedammonium chloride (15 mL) solution and ethyl acetate (3×15 mL). Thecombined organic extracts were washed with brine (20 mL), dried (Na₂SO₄)and concentrated in vacuo. The residue was purified by FCC, using 0-20%ethyl acetate in pentane, affording the title compound as a pale yellowoil (1.68 g, 64%). ¹H NMR (400 MHz, CDCl₃): 0.04 (6H, s), 0.84 (9H, s),1.48 (18H, m), 3.04 (2H, t), 3.79 (2H, t), 7.14-7.24 (2H, m), 7.42 (1H,s).

b. 2-[3-(5-Amino-3-tert-butyl-pyrazol-1-yl)phenylsulfanyl]-ethanol.(Intermediate 3b)

A mixture of Intermediate 3a (1.68 g, 3.37 mmol), pivaloyl acetonitrile(0.42 g, 3.37 mmol), and concentrated HCl solution (1.7 mL) in ethanol(10 mL) was heated under reflux for 3 h. After cooling, the pH wasadjusted to ca. 7 (using aqueous saturated NaHCO₃), and the mixturepartitioned between water (20 mL) and EtOAc (3×20 mL). The combinedorganic extracts were washed with brine (20 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by FCC, eluting with20-80% EtOAc in pentane, affording the title compound as a pale yellowoil (458 mg, 47%). LCMS (Method 1): Rt 2.35 min, m/z 292 [MH⁺].

c.{5-tert-Butyl-2-[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester. (Intermediate 3c)

Trichloroethyl chloroformate (0.1 mL, 0.78 mmol) was added to a solutionof Intermediate 3b (176 mg, 0.60 mmol) and DIPEA (0.31 mL, 1.81 mmol) inTHF (10 mL), and the mixture stirred for 3 h. The mixture was thenpartitioned between water (15 mL) and EtOAc (3×20 mL), and the combinedorganic extracts dried (Na₂SO₄) and concentrated in vacuo. The residuewas triturated (cyclohexane) and filtered to give the title compound asa yellow solid (280 mg, 100%). LCMS (Method 1): Rt 3.93 min, m/z 466/468[MH⁺]

d.1-{5-tert-Butyl-2-[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea.(Example 3)

A solution of Intermediate 1g (100 mg, 0.31 mmol) in DMF (2 mL) withDIPEA (165 μL, 0.97 mmol) and Intermediate 3c (145 mg, 0.31 mmol) washeated at 60° C. for 2 h. After cooling, the mixture was loaded on to aSCX-2 cartridge, eluting with MeOH then 2M NH₃ in MeOH, to afford thecrude product. Further purification by FCC, eluting with 0-10% [2M NH₃in MeOH] in DCM, followed by HPLC (elution with 30-95% MeCN in H₂O (0.1%HCO₂H)) gave the title compound as a colourless powder (45 mg). LCMS(Method 5): Rt 4.22 min, m/z 640 [MH⁺]. ¹H NMR (400 MHz, CDCl₃): 1.33(9H, s), 1.42-1.47 (6H, m), 1.89-1.97 (1H, m), 2.04-2.13 (2H, m),2.21-2.28 (1H, m), 3.09 (2H, m), 3.24 (1H, m), 3.73 (2H, m), 5.08 (1H,m), 5.19 (1H, m,), 5.78 (1H, m), 6.38 (1H, s), 6.92 (1H, br s), 7.01(1H, dd, J 1.92, 9.77), 7.24-7.34 (6H, m), 7.40-7.43 (2H, m), 7.54-7.75(2H, m).

Example 41-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.5-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate 4a)

DIAD (847 μL, 4.32 mmol) was added slowly to a solution of3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenol (for reference proceduresee US 2006/35922, which is incorporated herein by reference in itsentirety; 500 mg, 2.16 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (439μL, 3.25 mmol), and triphenylphosphine (1.13 g, 4.32 mmol) in THF (10.0mL) and stirred for 72 h. The reaction mixture was partitioned betweenEtOAc (75 mL) and H₂O (75 mL), and the aqueous layer extracted withEtOAc (3×). The combined organic layers were dried (MgSO₄), filtered andevaporated in vacuo. Purification by FCC, using 5-60% EtOAc incyclohexane, gave semi-pure title compound (1.26 g). This was used inthe next reaction without further purification. LCMS (Method 4): Rt2.77, m/z 360 [MH⁺].

b.(5-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 4b)

The title compound was prepared starting from2,2,2-trichloroethylchloroformate and Intermediate 4a by using ananalogous procedure to that described for Example 3 step c. LCMS (Method4): Rt 3.85, m/z 536 [MH⁺].

c.1-(5-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 4c)

The title compound was prepared starting from Intermediate 4b andIntermediate 1g by using an analogous procedure to that described forExample 1 step h. LCMS (Method 1): Rt 3.63 mins, m/z=708 [MH⁺].

d.1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 4)

Pyridinium para-toluene sulfonate (44.0 mg, 0.17 mmol) was added toIntermediate 4c (124 mg, 0.17 mmol) in MeOH (3.0 mL). After 2 h, furtherpyridinium para-toluene sulfonate (100 mg, 0.39 mmol) was added, and thereaction stirred for 12 h. The reaction was then heated to 55° C. for 2h, then cooled, and the solvent volume reduced to approximately ⅓ of itsvolume in vacuo. The residue was partitioned between EtOAc (50 mL) andsaturated NaHCO₃ (50 mL). The aqueous layer was extracted into EtOAc(3×), then the combined organic layers washed with brine, dried (MgSO₄)and evaporated in vacuo. The product was purified by FCC, using 0-10%MeOH in DCM, then further purified by HPLC (C18 X-select column, 10-98%MeCN in H₂O, 0.1% formic acid) to give the title compound (50.0 mg, 0.08mmol, 47%). LCMS (Method 5): Rt 4.04 mins, m/z 624 [MH⁺]. ¹H NMR (400MHz, CDCl₃): 1.30 (9H, s), 1.40-1.44 (3H, d, J=6.9 Hz), 1.44-1.47 (3H,d, J=6.9 Hz), 1.84-1.98 (1H, m), 2.00-2.10 (2H, m), 2.18-2.26 (1H, m),3.16-3.26 (1H, sp, J=6.9 Hz), 3.87-3.92 (2H, m), 4.03-4.07 (2H, m),5.01-5.09 (1H, td, J 8.9, 5.3 Hz), 5.14-5.17 (1H, t, J=4.0 Hz),5.47-5.52 (1H, br d, J=8.7 Hz), 6.29 (1H, s) 6.60 (1H, br s), 6.80-6.84(1H, m), 6.96-7.00 (1H, dd, J 9.9, 2.1 Hz), 7.07-7.11 (2H, m), 7.23-7.30(5H, m), 7.38-7.40 (1H, d, J=1.6 Hz), 7.53-7.57 (1H, d, J=9.9 Hz).

Example 51-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.2,2,2-Trifluoro-N-((1S,4S)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(Intermediate 5a)

Argon was bubbled through a solution of Intermediate 1b (8.00 g, 31.1mmol) and[N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium(Strem Chemicals Inc.; 0.06 g, 0.93 mmol) in dry DMF (100 mL) for 10min. A premixed combination of formic acid (2.4 mL, 62.2 mmol) and Et₃N(8.60 mL, 62.2 mmol) was added, and the mixture stirred at 50° C. for 24h. The mixture was cooled to room temperature and concentrated to ˜25mL. Water (70 mL) was added and the resulting precipitate filtered, andwashed with DCM (3×30 mL) and diethyl ether (30 mL) to leave a solid(4.75 g). The filtrate was decanted to leave a dark solid. Subsequentpurification by FCC using 0-30% EtOAc in cyclohexane gave a solid. Thiswas combined with the first obtained solid to give a beige solid (5.93g, 74%). ¹H NMR (400 MHz, d₆-DMSO): 1.60-1.83 (2H, m), 2.06-2.17 (2H,m), 4.60 (1H, m), 5.08 (1H, m), 5.28 (1H, d), 7.07 (1H, m), 7.25 (1H,ddd), 7.28 (1H, ddd), 7.50 (1H, dd), 9.78 (1H, d).

b. (1S,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol (Intermediate 5b)

To a grey solution of Intermediate 5a (5.55 g, 21.4 mmol) in MeOH (50mL), NaOH (1.28 g, 32.1 mmol) in water (15 mL) was added, and themixture stirred at room temperature for 3 days. NaOH (1.28 g, 32.1 mmol)was further added and the brown solution was stirred for 5 h. Thesolution was applied directly to an SCX-2 column, washing with MeOH andeluting with 2M NH₃ in MeOH, and concentrated under vacuum to leave agrey solid. The solid was suspended in DCM (50 mL) with sonication, thenfiltered and dried under vacuum to leave a pale grey solid (2.93 g,84%). ¹H NMR (400 MHz, d₆-DMSO): 1.41-1.64 (2H, m), 2.02-2.13 (2H, m),3.82 (1H, dd), 4.55 (1H, dd), 5.08 (1H, br s), 7.13-7.22 (2H, m),7.35-7.49 (2H, m).

c.(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 5c)

To a suspension of sodium hydride (60% in mineral oil, 1.07 g, 26.8mmol) in dry DMF (20 mL) at room temperature under nitrogen,Intermediate 5b (1.89 g, 11.6 mmol) was added portionwise over 2 min,and the resulting brown solution was stirred for 20 min. Intermediate 1f(1.60 g, 8.93 mmol) was added, and the solution stirred at 60° C. for 2h. The dark brown solution was cooled to room temperature andconcentrated under vacuum. The residue was purified by SCX-2, washingwith MeOH (200 mL) and eluting with 2M NH₃ in MeOH, to leave a darkbrown foam (3.21 g). Further purification by FCC, using 2-10% [2M NH₃ inMeOH] in DCM, gave a brown foam (2.11 g, 76%). ¹H NMR (400 MHz,d₆-DMSO): 1.37 (3H, d), 1.39 (3H, d), 1.59 (1H, m), 1.91 (1H, m), 2.11(1H, m), 2.33 (1H, m), 3.58 (1H, sept), 3.96 (1H, dd), 5.55 (1H, dd),7.18-7.37 (4H, m), 7.51 (1H, d), 7.68 (1H, d), 8.20 (1H, d).

d. (5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-carbamic acid2,2,2-trichloro-ethyl ester (Intermediate 5d)

To a suspension of 5-tert-butyl-[1,3,4]oxadiazol-2-ylamine (Atlantic,141 mg, 1.00 mmol) and Et₃N (279 μL, 2.00 mmol) in MeCN (2 mL),2,2,2-trichloroethyl chloroformate (207 μL, 1.50 mmol) was added in 4portions over 1 min at RT (CARE: exotherm to ˜40° C.). The resultingsuspension was stirred for 1 h. The suspension was filtered, washing thesolid with MeCN (3 mL), and concentrated to leave a yellow-brown paste.Purification by FCC, using 0-2.5% MeOH in DCM, gave a buff foam (232 mg,73%). ¹H NMR (400 MHz, CDCl₃): 1.42 (9H, s), 4.86 (2H, s).

e.1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 5)

A solution of Intermediate 5d (83.1 mg, 0.263 mmol), Intermediate 5c(80.6 mg, 0.250 mmol), and DIPEA (54.4 μL, 0.313 mmol) in DMF (2 mL) wasstirred at 125° C. for 45 min. After cooling, the mixture wasconcentrated in vacuo to give a brown oil. This was suspended in water(5 mL) and extracted with DCM (2×5 mL). The combined organics werepassed through a hydrophobic frit and concentrated under vacuum to leavea brown oil. Purification by FCC, using 0-8% MeOH in EtOAc, followed bytrituration (diethyl ether) afforded a buff solid (99.6 mg). Furtherpurification by HPLC (10-98% MeCN in H₂O, 0.1% HCO₂H) gave the titlecompound as a flocculent white solid (25.9 mg, 21%). LCMS (Method 5): Rt3.77 min, m/z 490 [MH⁺]. ¹H NMR (400 MHz, CDCl₃): 1.39 (9H, s), 1.52(3H, d), 1.55 (3H, d), 2.00 (1H, m), 2.21-2.36 (2H, m), 2.43 (1H, m),3.32 (1H, sept), 5.28-5.34 (2H, m), 7.12 (1H, dd), 7.30-7.38 (3H, m),7.47-7.50 (2H, m), 7.73 (1H, d), 8.35 (1H, br s), 8.49 (1H, br d).

Example 61-[(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea

a. 4-Nitro-1-p-tolyl-1H-pyrazole (Intermediate 6a)

To 4-tolylboronic acid (544 mg, 4.00 mmol), 4-nitropyrazole (226 mg,2.00 mmol), copper (II) acetate (545 mg, 3.00 mmol), and 4 Å sieves (1.5g) in DCM (15 mL), was added pyridine (0.32 mL, 4 mmol) at RT, andstirred for 5 h. The mixture was filtered through Celite, washing withDCM, then evaporated to dryness. The residue was purified by FCC,eluting with 0-30% ethyl acetate in cyclohexane, to give the titlecompound as a white solid (126 mg, 31%). LCMS (Method 3): Rt 3.93 min,m/z 204.1 [MH⁻].

b. 4-Amino-1-p-tolyl-1H-pyrazole (Intermediate 6b)

Intermediate 6a (212 mg, 1.04 mmol) was dissolved in ethanol (20 mL)then hydrogenated over 10% palladium on carbon for 4 h under hydrogenatmosphere. The mixture was then filtered through Celite, washing withethanol, and evaporated to dryness. The residue was purified by FCC,eluting with 0-10% MeOH in DCM, to give the title compound as a palebrown solid (154 mg, 86%). LCMS (Method 3): Rt 1.92 min, m/z 174.1[MH⁻].

c. (1-p-Tolyl-1H-pyrazol-4-yl)-carbamic acid 2,2,2-trichloro-ethyl ester(Intermediate 6c)

Intermediate 6b (150 mg, 0.87 mmol) dissolved in DCM (10 mL) was cooledusing an ice bath, and then treated sequentially with triethylamine(0.18 mL, 1.30 mmol) and trichloroethyl chloroformate (0.15 mL, 1.08mmol). The mixture was stirred with cooling for 45 min, then evaporatedto dryness. Residue was purified by FCC, eluting with 0-30% ethylacetate in cyclohexane, to give the title compound as a beige solid (286mg, 95%). LCMS (Method 3): Rt 4.25 min, m/z 348/350/352 [MH⁺].

d.1-[(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(1-p-tolyl-1H-pyrazol-4-yl)-urea(Example 6)

A solution of Intermediate 6c (65.0 mg, 0.19 mmol), Intermediate 5c(50.0 mg, 0.155 mmol), and DIPEA (0.127 mL, 0.8 mmol) in DMF (1 mL) washeated at 110° C. for 75 min and 50° C. for 64 h. After cooling, themixture was concentrated to dryness and the residue purified by FCC,eluting with 0-10% MeOH in DCM, to give the impure product (63 mg).Further purification by HPLC (Method 6) gave the title compound as awhite solid (45 mg, 56%). LCMS (Method 5): Rt 4.06 min, m/z 522.1 [MH⁺].¹H NMR (400 MHz, d₆-DMSO): 1.36-1.41 (6H, m), 1.76-1.85 (1H, m),1.98-2.08 (1H, m), 2.13-2.28 (2H, m), 2.33 (3H, s), 3.59 (1H, quintet, J6.8), 4.96-5.03 (1H, m), 5.62 (1H, t, J 4.6), 6.74 (1H, d, J 8.5), 7.24(1H, dd, J 9.9, 2.1), 7.26-7.46 (6H, m), 7.62-7.66 (2H, m), 7.68 (1H,s), 7.70 (1H, dd, J 9.9, 0.8), 8.24 (1H, br d), 8.26 (1H, s), 8.31 (1H,s).

Example 71-(4-Chloro-3-trifluoromethyl-phenyl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from4-chloro-3-(trifluoromethyl)aniline (Aldrich) by using analogousprocedures to those described for Example 5. LCMS (Method 5): Rt 4.72min, m/z 544 [MH⁺]; ¹H NMR (400 MHz, d₆-DMSO): 1.38 (3H, d), 1.40 (3H,d), 1.83 (1H, m), 2.04 (1H, m), 2.21 (2H, m), 3.58 (1H, sept), 5.00 (1H,m), 5.62 (1H, m), 6.84 (1H, d), 7.24 (1H, dd), 7.30-7.41 (3H, m), 7.44(1H, d), 7.56 (1H, d), 7.58 (1H, d), 7.70 (1H, d), 8.13 (1H, m), 8.24(1H, d), 8.83 (1H, s).

Example 81-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from3-tert-butyl-1,2,4-oxadiazol-5-amine (Enamine) using analogousprocedures to those described for Example 5. LCMS (Method 5): Rt 4.12min, m/z 490 [MH⁺]; ¹H NMR (400 MHz, CDCl₃): 1.25 (9H, s), 1.50 (3H, d),1.54 (3H, d), 1.99 (1H, m), 2.22-2.34 (2H, m), 2.52 (1H, m), 3.29 (1H,sept), 5.27 (1H, ddd), 5.36 (1H, dd), 7.16 (1H, dd), 7.32-7.41 (3H, m),7.49 (1H, d), 7.52 (1H, d), 7.75 (1H, dd), 8.64 (1H, d), 8.76 (1H, s).

Example 91-(1-tert-Butyl-1H-pyrazol-4-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from1-tert-butyl-1H-pyrazol-4-amine (Enamine) using analogous procedures tothose described for Example 5. LCMS (Method 5): Rt 3.50 min, m/z 488[MH⁺]; ¹H NMR (400 MHz, CDCl₃): 1.46 (3H, d), 1.49 (3H, d), 1.56 (9H,s), 1.89 (1H, m), 2.10-2.27 (2H, m), 2.38 (1H, m), 3.28 (1H, sept), 5.22(1H, ddd), 5.28 (1H, dd), 5.49 (1H, br s), 6.63 (1H, br s), 7.14 (1H,dd), 7.26-7.36 (3H, m), 7.39 (1H, d), 7.45 (1H, d), 7.48 (1H, m), 7.60(1H, d), 7.71 (1H, s).

Example 101-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 2-(5-Amino-3-tert-butyl-pyrazol-1-yl)-ethanol (Intermediate 10a)

A solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.00 g, 40.0 mmol),concentrated HCl (0.1 mL), and 2-hydrazino ethanol (2.98 mL, 44.0 mmol)in ethanol (40 mL) was refluxed for 20 h. The reaction mixture was thenconcentrated in vacuo. The resulting oily solid was washed withcyclohexane (30 mL), and dissolved in MeOH (5 mL) and H₂O (5 mL) andlyophilised to give the title compound as a white powder (7.13 g, 97%).LCMS (Method 3): Rt 0.43 min, m/z 184 [MH⁺].

b.5-tert-Butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-ylamine(Intermediate 10b)

A solution of Intermediate 10a (1.00 g, 5.46 mmol),tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol), and imidazole (774mg, 11.38 mmol) in DMF (9 mL) was stirred at RT under a nitrogenatmosphere for 18 h. Additional tert-butyl-dimethyl-chlorosilane (823mg. 5.46 mmol) and imidazole (774 mg, 11.38 mmol) were added to thereaction mixture and stirred for 6 h. The reaction mixture was dilutedwith NH₄Cl saturated aqueous solution (10 mL) and DCM (10 mL). Thelayers were separated and aqueous layer was extracted with DCM (3×10mL). The combined organic layers were dried (MgSO₄), filtered,concentrated in vacuo and purified by FCC, using 0-50% EtOAc incyclohexane, to give the title compound (1.15 g, 70%). LCMS (Method 3):Rt 3.06, 3.23 min, m/z 298 [MH⁺].

c.{5-tert-Butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 10c)

To a solution of Intermediate 10b (1.14 g, 3.85 mmol) and Et₃N (0.80 mL,5.77 mmol) in THF (38 mL), 2,2,2-trichloro chloroformate (583 μL, 4.23mmol) was added dropwise at 0° C. and then warmed to RT over 1 h. Thereaction mixture was left to stand for a further 18 h. The mixture wasdiluted NH₄Cl saturated aqueous solution (10 mL) and DCM (10 mL). Thelayers were separated and aqueous layer was extracted with DCM (3×10mL). The combined organic layers were dried (MgSO₄), filtered,concentrated in vacuo and purified three times by FCC, using 0-30% EtOAcin cyclohexane, to give the title compound as a yellow oil (354 mg,19%). Rf=0.6 (50% EtOAc in cyclohexane); ¹H NMR (300 MHz, CDCl₃): 0.02(s, 6H), 0.81 (s, 9H), 1.23 (s, 9H), 3.88 (t, J=4.5 Hz, 2H), 4.15 (t,J=4.5 Hz, 2H), 4.77 (s, 2H), 6.16 (s, 1H), 8.30 (br s, 1H).

d.1-{5-tert-Butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 10d)

A solution of Intermediate 10c (176 mg, 0.37 mmol), Intermediate 1g (100mg, 0.31 mmol), and DIPEA (0.16 mL, 0.93 mmol) in THF (2 mL) was heatedat 60° C. for 19 h. The reaction mixture was diluted with H₂O (5 mL) andDCM (5 mL). The layers were separated, and aqueous layer was extractedwith DCM (3×5 mL). The combined organic layers were dried (MgSO₄),filtered, concentrated in vacuo and then purified by FCC, using 0-5% [2MNH₃ in MeOH] in DCM, to give the title compound as a white powder (108mg, 19%). Rf=0.4 (5% [2M NH₃ in MeOH] in DCM); LCMS (Method 3): Rt 4.27min, m/z 646 [MH⁺].

e.1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 10)

To a solution of Intermediate 10d (100 mg, 0.15 mmol) in THF (2 mL),TBAF (1M in THF, 0.23 mL, 0.23 mmol) was added at RT and stirred for 10min. The reaction mixture was diluted with H₂O (5 mL) and DCM (5 mL).The layers were separated, and aqueous layer was extracted with DCM (3×5mL). The combined organic layers were dried (MgSO₄), filtered,concentrated in vacuo and then purified by FCC using 0-5% [2M NH₃ inMeOH] in DCM). The residue was washed with water and purified by HPLC(30%-100% MeCN in H₂O, 0.1% formic acid) to give the title compound as awhite powder (47 mg, 57%). Rf=0.2 (5% [2M NH₃ in MeOH] in DCM) LCMS(Method 5): Rt 3.59 min, m/z 532 [MH⁺]. ¹H NMR (400 MHz, CDCl₃): ¹H NMR(300 MHz, CDCl₃): 1.25 (s, 9H), 1.43 (d, J=6.9 Hz, 3H), 1.46 (d, J=6.9Hz, 3H), 1.92-2.30 (m, 4H), 3.25 (p, J=6.9 Hz, 1H), 3.95 (t, J=4.7 Hz,2H), 4.15 (dd, J=5.3, 3.5 Hz, 2H), 5.09-5.16 (m, 1H), 5.92 (d, J=8.0 Hz,1H), 6.12 (s, 1H), 6.92 (dd, J=9.8, 1.9 Hz, 1H), 7.22-7.27 (m, 2H), 7.33(td, J=5.8, 3.0 Hz, 1H), 7.40 (s, 1H), 7.43 (br s, 2H), 7.47 (d, J=7.8Hz, 1H), 7.70 (s, 1H).

Example 111-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from[4-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]methanol (for referenceprocedure see WO 2011/070368, which is incorporated herein by referencein its entirety) using analogous procedures to those described inExample 3. LCMS (Method 5): Rt 4.01 min, m/z 594.2 [MH⁺]; ¹H NMR (400MHz, CDCl₃): 1.30 (9H, s), 1.37-1.40 (3H, d, J=6.9 Hz), 1.40-1.43 (3H,d, J=6.9 Hz), 1.84-1.96 (1H, m), 2.00-2.10 (2H, m), 2.16-2.25 (1H, m),3.17-3.24 (1H, sp, J=6.9 Hz), 4.60 (2H, s), 5.01-5.09 (1H, td, J 9.0,5.6 Hz), 5.14-5.19 (1H, t, J=3.9 Hz), 5.70-5.78 (1H, br s), 6.32 (1H,s), 6.86 (1H, br s), 6.95 (1H, dd, J 9.8, 2.0 Hz), 7.23-7.31 (5H, m),7.39-7.46 (4H, m).

Example 121-{5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 1-(3-Bromo-benzyl)-4,4-difluoro-piperidine (Intermediate 12a)

A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol),4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), andpotassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) wasstirred at RT for 16 h. The mixture was filtered and evaporated, and theresidue partitioned between water (30 mL) and EtOAc (3×30 mL). Thecombined organic extracts were washed with water (2×50 mL) and dried(Na₂SO₄). The solvent was evaporated to give the title compound as acolourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292[MH⁺].

b. Di-tert-butyl1-{3-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}hydrazine-1,2-dicarboxylate(Intermediate 12b)

n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwiseto a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF(15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C.for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) wasadded in one portion. The mixture was stirred at −78° C. for 20 min,then allowed to warm to RT over 20 min. The mixture was then partitionedbetween saturated ammonium chloride solution (15 mL) and ethyl acetate(3×20 mL). The combined organic extracts were washed with brine (20 mL)and dried (Na₂SO₄). The solvent was evaporated and the residue purifiedby FCC, eluting with 0-100% EtOAc in pentane, to give the title compoundas a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z442 [MH⁺].

c.5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-ylamine.(Intermediate 12c)

A mixture of Intermediate 12b (1.30 g, 2.94 mmol), pivaloyl acetonitrile(0.37 g, 2.94 mmol), and concentrated HCl (1.5 mL) in ethanol (10 mL)was heated under reflux for 3 h. The cooled mixture was taken to ca. pH7 with aqueous saturated NaHCO₃, and the mixture partitioned betweenwater (15 mL) and EtOAc (3×15 mL). The combined organic extracts werewashed with brine (20 mL) and dried (Na₂SO₄). The solvent wasevaporated, and the residue purified by FCC, eluting with 0-100% EtOAcin pentane, to give the title compound as a pale yellow solid (450 mg,43%). LCMS (Method 1): Rt 1.93 min, m/z 349 [MH⁺].

d.{5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester. (Intermediate 12d)

2,2,2-Trichloroethyl chloroformate (0.077 mL, 0.57 mmol) was added to asolution of Intermediate 12c (200 mg, 0.57 mmol) and DIPEA (0.31 mL,1.81 mmol) in THF (5 mL), and the mixture stirred for 3 h. The mixturewas then partitioned between water (10 mL) and EtOAc (3×15 mL), and thecombined organic extracts dried (Na₂SO₄). The solvent was evaporated andthe residue triturated under pentane and filtered to give the titlecompound as a yellow solid (215 mg, 72%). LCMS (Method 1): Rt 2.89 min,m/z 523/525 [MH⁺]

e.1-{5-tert-Butyl-2-[3-(4,4-difluoro-piperidin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea.(Example 12)

The title compound was prepared using Intermediate 12d and Intermediate1g in an analogous procedure to that described in Example 1 step h. LCMS(Method 5): Rt 2.52 min, m/z 697 [MH⁺]; ¹H NMR (300 MHz, CDCl₃): 1.33(9H, s), 1.48 (6H, dd, J 7.0, 13.0 Hz), 1.90-2.15 (8H, m), 2.24-2.31(1H, m), 2.56 (4H, br s), 3.21-3.31 (1H, m), 3.59 (2H, br s), 5.06-5.13(1H, m), 5.18-5.21 (1H, m), 5.34 (1H, br s), 6.30 (1H, br s), 6.36 (1H,br s), 7.03-7.06 (1H, m), 7.29 (4H, br s), 7.39-7.47 (3H, m), 7.53 (1H,br s), 7.62-7.65 (1H, m).

Example 131-(5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea,formic acid salt

a. 5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (Intermediate13a)

4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 114 mmol) and4-methoxyphenyl hydrazine (19.89 g, 114 mmol) were dissolved in amixture of absolute ethanol (170 mL) and glacial acetic acid (5.0 mL)then heated to reflux for 3 h, before allowing to standing overnight atRT. The resulting red/brown solid was filtered off, and the filtrate wasthen diluted with water (500 mL), and basified with 880 ammonia solutionuntil the pH=5. This aqueous solution was extracted into diethyl ether(3×). The combined organics were dried (MgSO₄) and evaporated in vacuoto a brown oil. Trituration (pentane) gave the title compound as a lightpurple/brown solid (23.07 g, 94.1 mmol, 82%). LCMS (method 1): Rt 2.87min, m/z 246/247 [MH⁺].

b. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenol (Intermediate 13b)

Intermediate 13a (10.0 g, 40.8 mmol) was dissolved in DCM (80.0 mL), andaluminium trichloride (28.0 g, 204.0 mmol) was added portionwise. Thereaction was heated to reflux for 4 h. Additional aluminium trichloride(28.0 g, 204.0 mmol) was added portionwise, and the reaction heated atreflux overnight. After cooling, the mixture was carefully addedportionwise to saturated aqueous NaHCO₃ (300 mL). The mixture wasextracted with ethyl acetate (300 mL) and separated. The aqueous layerwas filtered under vacuo and acidified with 1N HCl until pH=7. Thisaqueous layer was then re-extracted into ethyl acetate, and the organicextracts were dried (MgSO₄) and evaporated in vacuo. Purification byFCC, using 0-40% EtOAc in DCM, gave the title compound (5.0 g, 21.6mmol, 53%). LCMS (method 1): Rt 2.77 min, m/z 232/233 [MH⁺].

c.5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate 13c)

To a solution of Intermediate 13b (1.15 g, 5.0 mmol),2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol), andtriphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL), was addeddiisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for75 min. The mixture was diluted with diethyl ether (50 mL) and extractedwith 10% aqueous citric acid soln (2×). The combined aqueous layers werebasified with solid potassium carbonate until pH=9. The aqueous layerwas then extracted with ethyl acetate (3×). The combined ethyl acetatelayers were washed with brine, dried (NaSO₄) and evaporated in vacuo.Purification by FCC using 0-12% [9:1 MeOH/880 ammonia] in DCM. Theresulting product was crystallised (diethyl ether) to give the titlecompound (270 mg, 0.756 mmol, 15%). LCMS (Method 1): Rt 2.31, 1.72 min,m/z 358/359 [MH⁺].

d.(5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-N,N-bis-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 13d)

Trichloroethylchloroformate (144 mg, 0.68 mmol) was added dropwise to asolution of Intermediate 13c (115 mg, 0.34 mmol) anddiisopropylethylamine (129 mg, 1.0 mmol) in THF (4 mL) and stirred for 2h. This mixture was diluted with ethyl acetate (25 mL) and washed withwater, brine and dried (MgSO₄) and evaporated in vacuo to gave the titlecompound (240 mg, 0.34 mmol, 100%). LCMS (method 1): Rt 3.02 min, m/z708 [MH⁺].

e.1-(5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea,formic acid salt (Example 13)

Intermediate 1g (95 mg, 0.295 mmol) and Intermediate 13d (175 mg, 0.33mmol) in a mixture of DMF (0.50 mL) and diisopropylethylamine (110 mg,0.85 mmol) were heated to 60° C. for 3 h. The solution was loaded ontoan SCX-2 cartridge, washing with MeOH and eluting with 2M NH₃ in MeOH.The resulting residue was purified by HPLC (C18 X-select column, 10-30%MeCN in H₂O, 0.1% formic acid) to give the title compound (15 mg, 6.4%).LCMS (Method 5): Rt 3.34 mins, m/z=706.4 [MH⁺]. ¹H NMR (400 MHz, CDCl₃):1.34 (9H, s), 1.48 (6H, dd, J 7.0, 16.4 Hz), 1.90-2.30 (4H, m), 2.40(3H, s), 2.75 (8H, br s), 2.91 (2H, t, J=5.3 Hz), 3.28 (1H, m), 4.11(2H, t, J=5.3 Hz), 5.10 (1H, m), 5.20 (1H, t, J=4.0 Hz), 6.16 (1H, brd), 6.39 (1H, s), 6.89 (2H, d, J=9.0 Hz), 7.04 (1H, dd, J 2.1, 10.0 Hz),7.18 (1H, br s), 7.25-7.34 (2H, m), 7.36-7.40 (3H, m), 7.47 (1H, m),7.60 (1H, d, J=10.1 Hz), 8.14 (1H, br s).

Example 141-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-benzonitrile (Intermediate 14a)

A cream suspension of 4-cyanophenylhydrazine hydrochloride (1.70 g, 10.0mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.31 g, 10.5 mmol) in EtOH(25 mL) was stirred at reflux for 4 h, then at RT for 64 h, and again atreflux for 24 h. The solution was cooled to RT, concentrated in vacuo,and partitioned between water (50 mL) and EtOAc (75 mL). The organicswere washed with brine (50 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to leave an orange solid (2.28 g, 95%). LCMS(Method 3): Rt 3.45 min, m/z 241 [MH⁺].

b. [5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester (Intermediate 14b)

To a suspension of Intermediate 14a (2.28 g, 9.49 mmol) in EtOAc (25 mL)and aq. NaOH solution (1M, 23.7 mL, 23.7 mmol) was added2,2,2-trichloroethyl chloroformate (1.57 mL, 11.4 mmol) dropwise over 2min. A precipitate formed which redissolved after 15 min, then theorange solution was stirred at RT for 90 min. 2,2,2-Trichloroethylchloroformate (0.391 mL, 2.85 mmol) was added, and the orange mixturestirred at RT for 16 h. The layers were separated, and the aqueousextracted with EtOAc (25 mL). The combined organics were washed withbrine (25 mL), dried (Na₂SO₄), filtered and concentrated in vacuo toleave an orange-red oil. Recrystallisation from cyclohexane gave anoff-white solid (3.12 g, 79%). LCMS (Method 3): Rt 4.46 min, m/z 415,417 [MH⁺].

c.1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea.(Example 14)

A solution of Intermediate 14b (61.6 mg, 0.148 mmol), Intermediate 5c(43.4 mg, 0.135 mmol), and DIPEA (0.029 mL, 0.169 mmol) in dioxane-DMF(3:1, 2.0 mL) was stirred at 60° C. for 18 h. Water (3 mL) was added,then the mixture extracted with DCM-MeOH (9:1, 2×3 mL). The combinedorganics were passed through a hydrophobic frit and concentrated invacuo to leave an orange oil. FCC, using 2-8% MeOH in DCM, gave thetitle compound as a white solid after freeze-drying (35.0 mg, 44%). LCMS(Method 5): Rt 4.46 min, m/z 589 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28(9H, s), 1.37 (3H, d, J 7.1), 1.39 (3H, d, J 7.1), 1.75 (1H, m), 2.01(1H, m), 2.09-2.22 (2H, m), 3.57 (1H, sept, J 6.9), 4.88 (1H, m), 5.58(1H, t, J 4.5), 6.38 (1H, s), 7.06 (1H, d, J 8.2), 7.23 (1H, dd, J 9.9,2.2), 7.27 (1H, d, J 7.3), 7.29-7.38 (2H, m), 7.42 (1H, d, J 7.5), 7.69(1H, dd, J 9.9, 0.9), 7.75 (2H, d, J 8.9), 7.96 (2H, d, J 8.7), 8.21(2H, s).

Example 151-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]methanol (for referenceprocedure see WO 2011/070368, which is incorporated herein by referencein its entirety) using analogous procedures to those described inExample 5. LCMS (Method 5): Rt 4.01 min, m/z 594.2 [MH⁺]. ¹H NMR (400MHz, d₆-DMSO): 1.27 (9H, s), 1.37 (3H, d, J 7.2), 1.38 (3H, d, J 7.2),1.74 (1H, m), 2.01 (1H, m), 2.11-2.16 (2H, m), 3.56 (1H, m), 4.55 (2H,d, J 3.1), 4.89 (1H, m), 5.29 (1H, s), 5.57 (1H, t, J 3.9), 6.33 (1H,s), 7.04 (1H, d, J 8.1), 7.22 (1H, dd, J 9.9, 2.1), 7.35-7.44 (8H, m),7.68 (1H, m), 8.02 (1H, s), 8.21 (1H, d, J 2.0).

Example 161-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 4-Hydrazino-piperidine-1-carboxylic acid benzyl ester (Intermediate16a)

A solution of 1-CBZ-4-piperidone (2.92 g, 12.5 mmol) and hydrazinehydrate (2.01 mL, 18.8 mmol) in MeOH (25 mL) was stirred at 50° C. for30 min, then cooled to RT and NaBH₄ (1.18 g, 31.3 mmol) added (CARE: gasevolution and exotherm to −45° C.). The solution was stirred at RT for30 min, then 50° C. for 18 h. The cooled solution was concentrated invacuo, suspended in water (25 mL) and extracted with DCM (2×25 mL). Thecombined organics were passed through a hydrophobic frit andconcentrated in vacuo to leave a clear oil. FCC, using 0-10% [2H NH₃ inMeOH] in DCM, gave the title compound as a clear oil (1.80 g, 58%). LCMS(Method 3): Rt 2.03 min, m/z 250 [MH⁺].

b. 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-piperidine-1-carboxylic acidbenzyl ester (Intermediate 16b)

A yellow solution of Intermediate 16a (1.80 g, 7.22 mmol),4,4-dimethyl-3-oxopentanenitrile (1.08 g, 8.66 mmol), and HCl (4M indioxane, 2.70 mL, 10.8 mmol) in EtOH (25 mL) was stirred at reflux for 4h. The cooled solution was applied to an SCX-2 cartridge (50 g), washedwith MeOH (100 mL). The product was eluted with 2M NH₃ in MeOH (100 mL);concentration in vacuo left a yellow oil (772 mg). FCC, using 0-5% MeOHin DCM, gave the title compound as a yellow gum (550 mg, 21%). LCMS(Method 3): Rt 2.88 min, m/z 357 [MH⁺].

c.4-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-piperidine-1-carboxylicacid benzyl ester (Intermediate 16c)

To a solution of Intermediate 16b (550 mg, 1.54 mmol) in aqueous NaOHsolution (1M, 3.85 mL, 3.85 mmol) and EtOAc (5 mL) at RT, was added2,2,2-trichloroethyl chloroformate (0.32 mL, 2.31 mmol) over 2 min, thenthe mixture stirred vigorously for min. The aqueous layer was extractedwith EtOAc (10 mL), then the combined organics washed with brine (10mL), dried (MgSO₄), filtered and concentrated in vacuo to leave ayellow-brown oil. FCC, using 0-30% EtOAc in cyclohexane, gave the titlecompound as a white foam (337 mg, 41%). LCMS (Method 3): Rt 4.81 min,m/z 531, 533 [MH⁺].

d.4-(3-tert-Butyl-5-{3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureido}-pyrazol-1-yl)-piperidine-1-carboxylicacid benzyl ester (Intermediate 16d)

A brown solution of Intermediate 16c (337 mg, 0.634 mmol), Intermediate1g (195 mg, 0.603 mmol), and DIPEA (0.131 mL, 0.754 mmol) in DMF (5 mL)was stirred at 100° C. for 90 min. The cooled solution was concentratedin vacuo, suspended in water (5 mL) and extracted with DCM (2×5 mL). Thecombined organics was passed through a hydrophobic frit and concentratedin vacuo to leave a brown gum. FCC, using 4.5% MeOH in DCM, gave thetitle compound as a yellow-brown oil (364 mg, 86%). LCMS (Method 3): Rt3.96 min, m/z 705 [MH⁺].

e.1-(5-tert-Butyl-2-piperidin-4-yl-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo-[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 16)

A suspension of Intermediate 16d (165 mg, 0.234 mmol), Pd/C (10%, 16mg), and 2M NH₃ in MeOH (0.117 mL, 0.234 mmol) in EtOH (5 mL) under N₂was evacuated and purged with H₂ twice, then stirred at rt for 8 h. Thesuspension was filtered through Celite, then the filter-cake washed withEtOH (10 mL). The combined organics were concentrated in vacuo to ˜0.5mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH(5 mL). The product was eluted with 2M NH₃ in MeOH (25 mL);concentration in vacuo left a pale yellow solid that was triturated withdiethyl ether (10 mL) to leave a buff solid (121 mg). Half of thismaterial was purified by HPLC(XBridge C18, 25-98% MeCN in H₂O, 0.1%NH₄OH) to give the title compound as a white solid after freeze-drying(20.0 mg, 15%). LCMS (Method 5): Rt 3.16 min, m/z 571 [MH⁺]. ¹H NMR (400MHz, d₆-DMSO): 1.16 (9H, s), 1.33 (3H, d, J 6.8), 1.35 (3H, d, J 6.8),1.68 (2H, m), 1.79 (2H, m), 1.91 (2H, m), 2.09 (2H, m), 2.47 (2H, m),2.98 (2H, d, J 12.3), 3.50 (1H, sept, J 6.8), 3.92 (1H, m), 4.82 (1H,m), 5.51 (1H, t, J 4.5), 5.97 (1H, s), 6.88 (1H, d, J 8.6), 7.14 (1H,dd, J 9.9, 2.1), 7.26 (1H, m), 7.31-7.38 (3H, m), 7.65 (1H, dd, J 9.8,0.8), 8.07 (1H, br s), 8.18 (1H, d, J 2.0).

Example 171-[5-tert-Butyl-2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

A mixture of Example 16 (half crude material, assume 64.8 mg, 0.114mmol) and formaldehyde (37% in water, 0.092 mL, 1.14 mmol) in DCM (2 mL)was stirred at RT for 10 min, then AcOH (0.013 mL, 0.227 mmol) andNaBH(OAc)₃ (48.1 mg, 0.227 mmol) were added sequentially, and thesolution stirred at RT for 3 h. The solution was concentrated in vacuoto ˜0.5 mL volume, applied to an SCX-2 cartridge (2 g) and washed withMeOH (15 mL). The product was eluted with 2M NH₃ in MeOH (10 mL);concentration in vacuo left a pale yellow solid (82.6 mg). HPLC (XBridgeC18, 30-98% MeCN in H₂O, 0.1% NH₄OH) gave the title compound as a whitesolid after freeze-drying (30.8 mg, 46%). LCMS (Method 5): Rt 3.18 min,m/z 585 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.21 (9H, s), 1.38 (H, d, J6.8), 1.40 (3H, d, J 6.8), 1.75 (2H, t, J 12.2), 1.91-2.04 (6H, m),2.07-2.17 (2H, m), 2.18 (3H, s), 2.87 (2H, d, J 10.6), 3.58 (1H, sept, J6.8), 3.88 (1H, m), 4.88 (1H, m), 5.56 (1H, t, J 4.7), 6.02 (1H, s),6.89 (1H, d, J 8.6), 7.19 (1H, dd, J 9.8, 2.1), 7.31 (1H, m), 7.36-7.43(3H, m), 7.70 (1H, d, J 9.8), 8.06 (1H, s), 8.22 (1H, d, J 2.0).

Example 181-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

To a stirred solution of Example 10 (136 mg, 0.26 mmol) and Et₃N (0.11mL, 0.77 mmol) in DCM (2.5 mL), was added mesyl chloride (31 μL, 0.31mmol) at 0° C. under N₂. After 15 min, the reaction mixture was warmedto RT. After 15 min, H₂O (5 mL) and DCM (5 mL) were added. The layerswere separated and aqueous layer was extracted with DCM. The combinedorganics were dried, filtered, concentrated in vacuo. The resultingresidue was dissolved in THF (2.5 mL), then DIPEA (49 μL, 0.28 mmol) andmorpholine (67 μL, 0.77 mmol) added sequentially. The resulting mixturewas heated at reflux for 21 h. The reaction mixture was cooled to RT,then H₂O (5 mL) and DCM (5 mL) were added. The layers were separated andaqueous extracted with DCM (3×5 mL). The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified byFCC, using 0-10% [2M NH₃ in MeOH] in DCM, and then prep HPLC (Gemini C18column, 20%-98% MeCN in H₂O, 0.1% HCO₂H, 20 min) to give the titlecompound as a white powder after freeze-drying (64 mg, 41%). LCMS(Method 5): Rt 3.21 min, m/z 601 [MH⁺]. ¹H NMR (400 MHz, CDCl₃): 1.22(9H, s), 1.47 (3H, d, J 6.9), 1.50 (3H, d, J 6.9), 2.00-2.12 (3H, m),2.25-2.31 (1H, m), 2.53-2.56 (4H, m), 2.68-2.70 (2H, m), 3.28 (1H, m),3.80 (4H, t, J 4.7), 4.16 (2H, t, J 4.7), 5.12-5.15 (1H, m), 5.20 (1H,d, J 4.2), 5.46 (1H, d, J 8.8), 5.89 (1H, s), 7.09 (1H, dd), 7.27-7.30(2H, m), 7.36-7.40 (1H, m), 7.45 (1H, d, J 2.0), 7.47 (1H, d, J 7.9),7.67 (1H, dd, J 9.9, 0.8), 9.43 (1H, s).

Example 191-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-7-fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. (1R,4S)-4-Amino-6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ol(Intermediate 19a)

To a solution of2,2,2-trifluoro-N-((1S,4R)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(synthesised in an analogous manner to that described in WO 2009/048474,which is incorporated herein by reference in its entirety) (2.31 g, 8.34mmol) in MeOH (22.5 mL), was added a solution of sodium hydroxide (0.834g, 20.8 mmol) in water (15 mL) and the mixture was stirred at RT for 65h. The mixture was concentrated in vacuo, then applied to an SCX-2cartridge (50 g), washing with methanol then eluting basic componentswith 0.2-1 M ammonia in methanol. Product containing fractions werecombined and concentrated in vacuo. The residue was purified by FCC,using 0-10% [2M NH₃ in MeOH] in DCM, to give the title compound (1.29 g,86%). ¹H NMR (300 MHz, d₆-DMSO): 1.60-2.15 (6H, m), 3.62-3.71 (1H, m),4.49 (1H, t, J 4.7), 5.15 (1H, br s), 6.98 (1H, dt, J 8.6, 2.8), 7.28(1H, dd, J 10.7, 2.8), 7.36 (1H, dd, J 8.6, 6.2).

b.(1S,4R)-7-Fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydronaphthalen-1-ylamine(Intermediate 19b)

Intermediate 19a (837 mg, 4.62 mmol) was dissolved in dry DMF (15 mL)under Ar, then NaH (60% in mineral oil, 556 mg, 13.9 mmol) was added,and the mixture stirred for 15 min. Intermediate if (893 mg, 4.99 mmol)was added, and the reaction heated at 60° C. for 2 h. The reaction wascooled, quenched by addition of water and extracted with DCM (4×30 mL).The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by FCC,eluting with 0-20% [2M NH₃ in MeOH] in DCM, to give the title compound(429 mg, 27%). LCMS (Method 3): Rt 1.96, m/z 363 [MNa⁺].

c.1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[(1S,4R)-7-fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 19)

Intermediate 19b (85.0 mg, 0.250 mmol) and(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (US2004/192653, 99 mg, 0.300 mmol) weredissolved in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.400 mmol). Thereaction was heated at reflux for 1.75 h, then more(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (35 mg, 0.100 mmol) and DIPEA (3 drops) wereadded. After a further 4 h the mixture was concentrated in vacuo. Theresidue was purified by FCC, using 0-15% MeOH in DCM, to give impureproduct (82 mg). Further purification twice by HPLC (C18 X-selectcolumn, 40-98% MeCN in H₂O, 0.1% HCO₂H) gave the title compound as awhite powder after freeze-drying (44 mg, 34%). LCMS (Method 5): Rt 3.83min, m/z 520.1 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.21 (9H, s), 1.35-1.43(6H, m), 1.85-2.25 (4H, m), 3.51-3.62 (4H, m), 4.80-4.91 (1H, m),5.50-5.57 (1H, m), 6.02 (1H, s), 7.09 (1H, d, J 8.8), 7.11-7.17 (2H, m),7.20 (1H, dd, J 9.6, 2.2), 7.44-7.50 (1H, m), 7.69 (1H, d, J 9.6), 8.22(1H, br d), 8.40 (1H, s).

Example 201-[(1S,4R)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea

a. (2-p-Tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester(Intermediate 20a)

NaOH (107 mg, 2.67 mmol) was added to a stirred solution of2-p-tolyl-2H-pyrazol-3-ylamine (for reference procedure see WO2009/150614, which is incorporated herein by reference in its entirety,346 mg, 2.00 mmol) in water (1 mL) and EtOAc (4 mL). The mixture wascooled to 0° C., and 2,2,2-trichloroethyl chloroformate (385 L, 2.80mmol) added. Stirring was continued for 30 min at 0° C. and then for 2 hat RT. The mixture was partitioned between water and EtOAc. The organicphase was washed with brine and concentrated to dryness in vacuo to givethe title compound as an orange residue. LCMS (Method 3): Rt 3.90 min,m/z 348, 350 [MH⁺].

b.1-[(1S,4R)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(2-p-tolyl-2H-pyrazol-3-yl)-urea(Example 20)

A mixture of Intermediate 1g (50.0 mg, 0.16 mmol), Intermediate 20a(54.0 mg, 0.16 mmol), and DIPEA (54.0 μL, 0.31 mmol) in DMF (2.5 mL) washeated to 100° C. for 1 h. After cooling, the mixture was partitionedbetween EtOAc and water, and then extracted into EtOAc (3×). Thecombined organic extracts were washed with sat. aq. NaHCO₃ solution,brine, and evaporated in vacuo. The residue was purified by FCC, using0-10% [2M NH₃ in MeOH] in DCM, to give a beige solid (30 mg). Furtherpurification by HPLC (5-98% MeCN in H₂O, 0.1% HCO₂H) gave the titlecompound as a white solid after freeze-drying (17 mg, 20%). LCMS (Method5): Rt 3.68 min, m/z 522 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.35-1.40(6H, m), 1.81-1.98 (2H, m), 2.02-2.15 (2H, m), 2.37 (3H, s), 3.57 (1H,sept, J 6.6), 4.83 (1H, m), 5.52 (1H, t, J 4.2), 6.40 (1H, d, J 1.8),7.16 (1H, dd, J 9.6, 2.2), 7.21-7.42 (8H, m), 7.51 (1H, d, J 1.8), 7.67(1H, d, J 9.6), 8.20 (1H, m), 8.29 (1H, m), 8.45 (1H, br s).

Example 211-(1-tert-Butyl-1H-pyrazol-4-yl)-3-[(1S,4R)-7-fluoro-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared starting from1-tert-butyl-1H-pyrazol-4-amine (Enamine) and Intermediate 19b usinganalogous procedures to those described for Example 5. LCMS (Method 5):Rt 3.65 min, m/z 506.2 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.36-1.42 (6H,m), 1.49 (9H, s), 1.84-2.25 (4H, m), 3.57 (1H, sept, J 7.0), 4.80-4.89(1H, m), 5.50-5.55 (1H, m), 6.72 (1H, d, J 8.8), 7.09-7.21 (3H, m), 7.37(1H, d, J 0.8), 7.43-7.49 (1H, m), 7.69 (1H, d), 7.77 (1H, d), 8.14 (1H,s), 8.21 (1H, d).

Example 221-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt

a. 5-tert-Butyl-2-(3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-ylamine(Intermediate 22a)

Triisopropylsilylchloride (1.02 mL, 3.96 mmol) was added to a solutionof 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (915 mg, 3.96 mmol) andimidazole (646 mg, 9.50 mmol) in DMF (15 mL) at 0° C. The reaction wasstirred at RT over the weekend then partitioned between EtOAc and water.The aqueous layer was then extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andevaporated in vacuo. The residue was purified by FCC, using 0-40% EtOAcin cyclohexane, to give the title compound (1.53 g, 99%). LCMS (Method4): Rt 4.78 min, m/z 388 [MH⁺].

b.[5-tert-Butyl-2-(3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 22b)

2,2,2-Trichloroethylchloroformate (1.09 mL, 7.92 mmol) was added to asolution of Intermediate 22a (1.53 g, 3.96 mmol) and DIPEA (2.75 mL,15.8 mmol) in THF (40 mL) at 0° C. The reaction was stirred at RT for 3h then partitioned between EtOAc and water. The aqueous layer was thenextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified by FCC, using 0-50% EtOAc in cyclohexane, to give the titlecompound (2.22 g, 99%). LCMS (Method 4): Rt 5.55 min, m/z 560, 562[MH⁺].

c.1-[5-tert-Butyl-2-(3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 22c)

Intermediate 22b (390 mg, 0.69 mmol) was added to a solution ofIntermediate 1g (223 mg, 0.69 mmol) and DIPEA (240 μL, 1.38 mmol) in1,4-dioxane (6.0 mL). The reaction was heated to 60° C. for 3 h andheated at 45° C. overnight. The reaction was cooled and partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×). The combined organic layers were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo. The residue was purified by FCC, using0-10% MeOH in DCM, to give the title compound (258 mg, 50%). LCMS(Method 2): Rt 4.93 min, m/z 736 [MH⁺].

d.1-[5-tert-Butyl-2-(3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 22d)

TBAF (1M in THF, 350 μL, 0.35 mmol) was added to a solution ofIntermediate 22c (258 mg, 0.35 mmol) in THF (5.0 mL) at 0° C. Thereaction was stirred for 1 h then partitioned between EtOAc and water.The aqueous layer was then extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andevaporated in vacuo. The residue was purified by FCC, using 0-10% MeOHin DCM, to give the title compound as an off-white solid (150 mg, 75%).LCMS (Method 1): Rt 4.11 min, m/z 580 [MH⁺]. ¹H NMR (400 MHz, d₄-MeOD):1.30 (9H, s), 1.42 (3H, d, J 6.9), 1.45 (3H, d, J 6.9), 1.88-2.16 (3H,m), 2.20-2.30 (1H, m), 3.51 (1H, sept, J 6.9), 4.90 (1H, dd, J 8.9,5.6), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 6.84 (1H, ddd, J 8.3, 2.6,0.8), 6.88-6.94 (2H, m), 7.19-7.26 (2H, m), 7.26-7.33 (4H, m), 7.61 (1H,d, J 10.0), 8.01 (1H, s).

e.1-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaFormate Salt (Example 22)

DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d(75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19mmol), and Ph₃P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. Thereaction was stirred at RT over the weekend then partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by FCC, using 0-10%[2M NH₃ in MeOH] in DCM. Further purification by HPLC (C18 X-selectcolumn, 25-98% MeCN in H₂O, 0.1% HCO₂H) gave the title compound as awhite powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32min, m/z 707.4 [MH⁺]. ¹H NMR (400 MHz, d₄-MeOD): 1.31 (9H, s), 1.42 (3H,d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m),2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H,m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89(1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd,J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H,m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7),8.42 (1H, br s).

Example 231-[5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 2-(3-Bromo-phenyl)-5-tert-butyl-2H-pyrazol-3-ylamine (Intermediate23a)

A mixture of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.4 mmol)and 4,4-dimethyl-3-oxo-pentanenitrile (4.29 g, 33.6 mmol) in absoluteethanol (55 mL) was stirred at reflux for 18 h and cooled, thenconcentrated in vacuo. The residue was suspended in sat. aq. NaHCO₃ (50mL) and extracted with EtOAc (3×50 mL). The combined organics were dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by FCC,using 0-5% [2M NH₃ in MeOH] in DCM, to give the title compound (3.56 g,54%). LCMS (Method 1): Rt 3.33 min, m/z 294, 296 [MH⁺].

b.Di-tert-butyl(1-(3-bromophenyl)-3-tert-butyl-1H-pyrazol-5-yl]imidodicarbonate(Intermediate 23b)

To a solution of Intermediate 23a (1.50 g, 5.10 mmol) andN,N-dimethyl-4-aminopyridine (31 mg, 0.26 mmol) in DCM (30 mL), wasadded di-tert-butyl dicarbonate (3.33 g, 15.3 mmol), and the mixture wasstirred at RT for 20 h. The mixture was diluted with DCM, washed withwater, then dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by FCC, using 0-2.5% MeOH in DCM, to give the titlecompound (1.97 g, 78%). ¹H NMR (400 MHz, d₄-MeOH): 1.33 (27H, s), 6.13(1H, s), 7.25 (1H, d J 3.9), 7.28 (1H, d J 8.0), 7.35-7.40 (1H, m),7.41-7.47 (1H, m).

c. [5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl]-carbamicacid tert-butyl ester (Intermediate 23c)

A mixture of Intermediate 23b (900 mg, 1.80 mmol), morpholine (240 mg,2.70 mmol), potassium-tert-butoxide (303 mg, 2.70 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl (87 mg, 0.18mmol), and tris(dibenzylideneacetone)dipalladium(0) (81 mg, 0.09 mmol)in THF (9 mL) was irradiated in the microwave at 100° C. for 20 min. Thereaction was diluted with water and extracted with EtOAc (×2). Thecombined organics were washed with brine, dried (MgSO₄), filtered andevaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAcin cyclohexane, to give the title compound (290 mg, 40%). LCMS (Method7): Rt 3.94 min, m/z 401 [MH⁺].

d. 5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-ylamine(Intermediate 23d)

A solution of Intermediate 23c (290 mg, 0.725 mmol) and TFA (3 mL) inDCM (4 mL) was stirred at RT for 1 h. The reaction mixture was appliedto an SCX-2 cartridge (10 g) and washed with MeOH. The product waseluted with 2M NH₃ in MeOH; concentration in vacuo gave the titlecompound (190 mg, 86%). LCMS (Method 1): Rt 2.29 min, m/z 301 [MH⁺].

e. [5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 23e)

2,2,2-Trichloroethylchloroformate (175 mg, 0.82 mmol) was added dropwiseto a solution of Intermediate 23d (190 mg, 0.63 mmol) and DIPEA (244 mg,1.89 mmol) in THF (10 mL), and the mixture stirred at RT for 1.5 h. Themixture was diluted with water and extracted with EtOAc (×2). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by FCC, using 0-50%EtOAc in cyclohexane, to give the title compound (140 mg, 46%). LCMS(Method 4): Rt 3.94, m/z 475 [MH⁺].

f.1-[5-tert-Butyl-2-(3-morpholin-4-yl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 23)

A solution of Intermediate 1g (64 mg, 0.20 mmol), Intermediate 23e (140mg, 0.29 mmol), and DIPEA (103 mg, 0.80 mmol) in DMF (2 mL) was stirredat 60° C. for 1 h. The reaction mixture was applied to an SCX-2cartridge (25 g) and washed with MeOH. The product was eluted with 2MNH₃ in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2MNH₃ in MeOH] in DCM, followed by HPLC (C6-Ph column, 10-70% MeCN in H₂O,0.1% HCO₂H) gave the title compound as a white powder afterfreeze-drying (46 mg, 38%). LCMS (Method 5): Rt 4.39 min, m/z 649.2[MH⁺]. ¹H NMR (400 MHz, d₄-MeOH): 1.30 (9H, s), 1.44 (6H, m), 1.85-2.05(2H, m), 2.05-2.16 (1H, m), 2.19-2.29 (1H, m), 3.15 (4H, t, J 3.8),3.47-3.56 (1H, m), 3.76 (4H, t, J 4.9), 4.86-4.92 (1H, m), 5.44 (1H, t,J 4.3), 6.32 (1H, s), 6.91 (1H, d, J 8.1), 7.00-7.05 (2H, m), 7.19-7.38(6H, m), 7.60 (1H, d, J 9.5), 8.00 (1H, d, J 1.6).

Example 241-{5-tert-Butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.5-tert-Butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-ylamine(Intermediate 24a) and5-tert-Butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-ylamine(Intermediate 24b)

A solution of 5-tert-butyl-2-(1H-indazol-6-yl)-2H-pyrazol-3-ylamine(US2008/113967, 200 mg, 0.78 mmol) was formed in DMF (10 mL).4-(2-chloroethyl)morpholine hydrochloride salt (160 mg, 0.86 mmol) andK₂CO₃ (276 mg, 2.0 mmol) were added, and the mixture heated at 50° C.overnight. The mixture was allowed to cool to RT then partitionedbetween EtOAc/water and extracted with EtOAc. The combined organics weredried over Na₂SO₄, filtered and concentrated in vacuo. Purification byFCC, using 0-10% MeOH in EtOAc, gave two products. First eluting:5-tert-butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-ylamine(Intermediate 24a; 134 mg, 57%) as a yellow solid. LCMS (Method 1): Rt1.81, m/z 369 [MH⁺]. Second eluting:5-tert-butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-ylamine(Intermediate 24b; 86 mg, 30%) as a yellow solid. LCMS (Method 1): Rt1.68, m/z 369 [MH⁺]. Regioisomer structure confirmation using ¹H NMRnOe.

b.{5-tert-Butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 24c)

A solution of Intermediate 24a (134 mg, 0.36 mmol) was formed in THF (10mL). DIPEA (125 μL, 0.72 mmol) was added followed by the dropwiseaddition of a solution of 2,2,2-trichloroethylchloroformate (50 μ□L,0.36 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, thenpartitioned between EtOAc/water and extracted with EtOAc. The combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by FCC, using 0-10% MeOH in EtOAc, gave the title compound(200 mg, 99%) as a colourless film. LCMS (Method 4): Rt 2.59, m/z 543,545 [MH⁺].

c.1-{5-tert-Butyl-2-[1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 24)

The title compound was prepared as an off-white solid (65 mg, 50%) usingIntermediate 1g (71 mg, 0.22 mmol) and Intermediate 24c (100 mg, 0.18mmol) in a similar manner to Example 1. LCMS (Method 5): Rt 3.40 min,m/z 717 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.30 (9H, s), 1.37 (3H, d, J6.9), 1.38 (3H, d, J 6.9), 1.80-1.97 (2H, m), 2.05-2.10 (2H, m), 2.41(4H, br s), 2.75 (2H, br s), 3.49 (4H, br s), 3.56 (1H, sept, J 6.9),4.52 (2H, m), 4.79-4.85 (1H, m), 5.52 (1H, t, J 4.5), 6.40 (1H, s), 7.06(1H, d, J 8.5), 7.13 (1H, dd, J 9.7, 2.0), 7.22-7.29 (4H, m), 7.36-7.39(1H, m), 7.68 (1H, d, J 9.7), 7.83 (1H, s), 7.87 (1H, d, J 8.5),8.13-8.19 (3H, m).

Example 251-{5-tert-Butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.{5-tert-Butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 25a)

To a solution of Intermediate 24b (86 mg, 0.23 mmol) in THF (10 mL) wasadded DIPEA (80 μL, 0.46 mmol), followed by the dropwise addition of asolution of 2,2,2-trichloroethylchloroformate (32 μL, 0.23 mmol) in THF(2 mL). The mixture was stirred at RT for 4 h, then partitioned betweenEtOAc/water and extracted with EtOAc. The combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by FCC,using 0-20% MeOH in EtOAc, gave the title compound (32 mg, 26%) as ayellow solid. LCMS (Method 4): Rt 2.64, 0.2 m/z 543, 545 [MH⁺].

b.1-{5-tert-Butyl-2-[2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-yl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 25)

The title compound was prepared as an off-white solid (16 mg, 47%) usingIntermediate 1g (23 mg, 0.07 mmol) and Intermediate 25a (32 mg, 0.06mmol) in a similar manner to example 1. LCMS (Method 5): Rt 3.43 min,m/z 717 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.29 (9H, s), 1.37 (3H, d, J6.1), 1.38 (3H, d, J 6.1), 1.81-1.97 (2H, m), 2.03-2.13 (2H, m), 2.42(4H, t, J 4.3), 2.85 (2H, t, J 6.3), 3.50-3.60 (5H, m), 4.56 (2H, t, J6.3), 4.80-4.86 (1H, m), 5.52 (1H, t, J 4.3), 6.36 (1H, s), 7.11 (1H, d,J 8.5), 7.14-7.19 (2H, m), 7.25-7.30 (3H, m), 7.36-7.39 (1H, m), 7.65(1H, m), 7.68 (1H, d, J 9.8), 7.83 (1H, d, J 9.0), 8.16 (1H, s), 8.20(1H, m), 8.48 (1H, s).

Example 261-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

a. [5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester (Intermediate 26a)

To a mixture of Intermediate 10a (367 mg, 2.0 mmol) in water (1 mL) andEtOAc (4 mL), was added NaOH (107 mg, 2.67 mmol) followed by2,2,2-trichloro chloroformate (385 μL, 2.80 mmol). The reaction mixturewas stirred at RT for 2 h and then diluted with additional EtOAc. Theorganic layer was washed with water followed by brine, dried andconcentrated in vacuo. The resultant residue was purified by FCC, using0-80% EtOAc in DCM to afford the title compound (466 mg, 65%) as acolourless oil which solidified on standing. LCMS (Method 3): Rt 3.73min, m/z 358, 360 [MH⁺].

b. 2,6-Dichloro-benzoic acid N′-(5-fluoro-pyridin-2-yl)-hydrazide(Intermediate 26b)

DIPEA (2.73 mL, 15.7 mmol) was added dropwise to a solution of(5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO2010/022076, which is incorporated herein by reference in its entirety;1.0 g, 7.87 mmol) and 2,6-dichloro-benzoyl (1.65 g, 7.87 mmol) in DCM(50 mL). The reaction mixture was stirred at RT for 30 min and thensuspended in DCM and water. The resulting suspension was filtered andthe solid was collected by filtration, washed with water and air driedto afford the title compound (1.66 g, 71%) as a white solid. LCMS(Method 3): Rt 3.04 min, m/z 300, 302 [MH⁺].

c. 3-(2,6-Dichloro-phenyl)-6-fluoro-[1,2,4]triazolo[4,3-a]pyridine(Intermediate 26c)

Hexachloroethane (2.60 g, 11.0 mmol) was added portionwise over 5 min atRT to a stirred mixture of Intermediate 26b (1.65 g, 5.50 mmol),triphenylphosphine (2.88 g, 11.0 mmol), and triethylamine (3.06 mL, 22.0mmol) in THF (50 mL). The reaction mixture was stirred at RT for 18 hand then allowed to stand at RT for 72 h. The resulting suspension wasfiltered and the filtrate was concentrated in vacuo and purified by FCCusing SCX-2 cartridge. The cartridge was washed with MeOH, and theproduct was eluted with 2M NH₃ in MeOH to give the title compound (1.44g, 93%) as a beige solid. LCMS (Method 3): Rt 3.08 min, m/z 282, 284[MH⁺].

d.(1S,4R)-4-[3-(2,6-Dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 26d)

Intermediate 1d (404 mg, 2.48 mmol) was added to a stirred solution ofsodium hydride (60% in mineral oil, 298 mg, 7.44 mmol) in anhydrous DMF(15 mL) at RT under an argon atmosphere. The reaction mixture wasstirred at RT for 15 min, then Intermediate 26c (0.70 g, 2.48 mmol) wasadded, and stirring at 60° C. was continued for 1 h. After cooling, thereaction mixture was quenched by careful addition of a saturated aqueoussolution of NH₄Cl and water (1:1) and extracted with EtOAc (×3). Thecombined organic layers were washed with a saturated aqueous solution ofNaHCO₃ followed by brine, dried and concentrated in vacuo. The resultantresidue was purified by FCC, using 0-20% [2M NH₃ in MeOH] in DCM toafford the title compound (345 mg, 33%) as a brown residue. LCMS (Method3): Rt 2.34 min, m/z 425, 427. [MH⁺].

e.1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Example 26)

A mixture of Intermediate 26a (100 mg, 0.279 mmol), Intermediate 26d(108 mg, 0.254 mmol), and DIPEA (73 μL, 0.419 mmol) in dioxane (2.5 mL)was stirred at 60° C. for 42 h and then left standing at RT for 72 h.The volatiles were concentrated in vacuo and the resultant residue waspurified by FCC, using 0-10% MeOH in DCM followed by MDAP (Method 7) toafford the title compound (23 mg, 14%) as a white solid. LCMS (Method5): Rt 4.19 min, m/z 634 [MH⁺]. ¹H NMR (400 MHz, DMSO): 1.21 (9H, s),1.79-2.16 (4H, m), 3.62-3.70 (2H, m), 3.94 (2H, t, J=6.0 Hz), 4.78-4.88(1H, m), 4.99 (1H, br s), 5.55 (1H, t, J=4.2 Hz), 6.05 (1H, s), 7.07(1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.31-7.38 (4H, m), 7.70-7.74 (1H,m), 7.74-7.80 (2H, m), 7.91 (1H, d, J=9.9 Hz), 7.98 (1H, d, J=2.1 Hz),8.19 (1H, s).

Example 271-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaFormate Salt

To a stirred solution of Example 26 (38 mg, 0.06 mmol) andmethanesulfonyl chloride (7.0 μL, 0.09 mmol) in DCM (1 mL), was addedDIPEA (31 μL, 0.18 mmol). The reaction mixture was stirred at RT 1 h,then diluted with DCM, washed with water followed by a saturated aqueoussolution of NaHCO₃ and brine, dried and concentrated in vacuo. Theresultant residue was dissolved in THF (2 mL) and treated withmorpholine (26 μL, 0.30 mmol). The reaction mixture was heated at 60° C.for 18 h, then the volatiles were concentrated in vacuo. The resultantresidue was partitioned between DCM and water. The organic layer waswashed with brine, dried and concentrated in vacuo. The resultantresidue was purified by MDAP (Method 7) to afford the title compound (13mg, 30%) as an off white solid. LCMS (Method 5): Rt 3.56 min, m/z 703[MH⁺]. ¹H NMR (400 MHz, DMSO): 1.20 (9H, s), 2.15-1.82 (4H, m),2.41-2.35 (4H, m), 2.61 (2H, t, J=7.1 Hz), 3.53 (4H, t, J=4.6 Hz), 3.98(2H, t, J=7.1 Hz), 4.79-4.88 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.02 (1H,s), 6.95 (1H, d, J=8.6 Hz), 7.24-7.30 (1H, m), 7.31-7.39 (4H, m),768-7.80 (3H, m), 7.91 (1H, d, J=9.9 Hz), 7.98 (1H, d, J=2.1 Hz), 8.24(2H, s).

Example 281-[5-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaFormate Salt

a. Methanesulfonic acid2-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-ethylester (Intermediate 28a)

A mixture of Example 26 (350 mg, 0.55 mmol), methanesulfonyl chloride(55 μL, 0.72 mmol), and DIPEA (288 μL, 1.65 mmol) in DCM (4 mL) wasstirred at RT for 45 min. Additional amount of methanesulfonyl chloride(15 μL) was added, and stirring was continued for 30 min. Additionalamount of methanesulfonyl chloride (15 μL) was added and stirring wascontinued for 20 min. The reaction mixture was partitioned between DCMand water. The organic layer was washed with brine, dried through aphase separator and concentrated in vacuo to afford the title compound(0.33 g, 84%) as a pale yellow solid. LCMS (Method 3): Rt 3.77 min, m/z712, 714. [MH⁺].

b.1-[5-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Example 28)

A mixture of Intermediate 28a (110 mg, 0.15 mmol) and dimethylamine(2.0M in THF, 1.54 mL, 3.09 mmol) in anhydrous THF (2 mL) was stirred at60° C. for 18 h in a sealed vial. The volatiles were concentrated invacuo and the resultant residue was purified by MDAP (Method 7) toafford the title compound (44 mg, 43%). LCMS (Method 5): Rt 3.50 min,m/z 661 [MH⁺]. ¹H NMR (400 MHz, DMSO): 1.19 (9H, s), 1.83-2.14 (4H, m),2.18 (6H, s), 2.59 (2H, t, J=6.9 Hz), 3.96 (2H, t, J=6.9 Hz), 4.79-4.87(1H, m), 5.53 (1H, t, J=4.0 Hz), 6.01 (1H, s), 6.92 (1H, d, J=8.7 Hz),7.22-7.28 (1H, m), 7.30-7.38 (4H, m), 7.68-7.78 (3H, m), 7.90 (1H, dd,J=9.9, 0.8 Hz), 7.96 (1H, d, J=2.0 Hz), 8.15 (1H, s), 8.44 (1H, s).

Example 291-[5-tert-Butyl-2-(2-piperidin-1-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaFormate Salt

The title compound was prepared starting from Intermediate 28a andpiperidine using analogous procedures to those described in Example 28.LCMS (Method 5): Rt 3.73 min, m/z 701 [MH⁺]. ¹H NMR (400 MHz, DMSO):1.20 (9H, s), 1.30-1.39 (2H, m), 1.51-1.41 (4H, m), 1.81-2.16 (4H, m),2.34-2.43 (4H, m), 2.60 (2H, t, J=7.1 Hz), 3.97 (2H, t, J=7.1 Hz),4.79-4.88 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.02 (1H, s), 6.92 (1H, d,J=8.6 Hz), 7.20-7.31 (1H, m), 7.31-7.39 (4H, m), 7.69-7.79 (3H, m), 7.91(1H, dd, J=9.9, 0.8 Hz), 7.97 (1H, d, J=2.0 Hz), 8.16 (1.5H, s), 8.28(1H, s).

Example 301-{5-tert-Butyl-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaFormate Salt

The title compound was prepared starting from Intermediate 28a and1-methyl-piperazine using analogous procedures to those described inExample 28. LCMS (Method 5): Rt 3.41 min, m/z 716.5 [MH⁺]. ¹H NMR (400MHz, DMSO): 1.20 (9H, s), 1.82-2.12 (4H, m), 2.14 (3H, s), 2.25-2.45(8H, m), 2.60 (2H, t, J=7.15 Hz), 3.96 (2H, t, J=7.1 Hz), 4.79-4.88 (1H,m), 5.55 (1H, t, J=4.2 Hz), 6.02 (1H, s), 6.90 (1H, d, J=8.6 Hz),7.24-7.30 (1H, m), 7.31-7.40 (4H, m), 7.68-7.79 (3H, m), 7.91 (1H, d,J=9.9 Hz), 7.98 (1H, d, J=2.0 Hz), 8.16 (1.5H, s), 8.22 (1H, s).

Example 311-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

a. 2-Chloro-benzoic acid N′-(5-fluoro-pyridin-2-yl)-hydrazide(Intermediate 31a)

To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for referenceprocedure see WO 2010/022076, which is incorporated herein by reference;1.0 g, 7.87 mmol) and 2-chloro-benzoyl chloride (1 mL, 7.87 mmol) in DCM(50 mL) was added dropwise DIPEA (2.74 mL, 15.75 mmol). The reactionmixture was stirred at RT for 1 h then washed with water. The organiclayer was dried through a phase separator and then concentrated in vacuoto afford the title compound (1.95 g, 93%) as a brown solid. LCMS(Method 3): Rt 2.82 min, m/z 266 [MH⁺].

b. 3-(2-Chloro-phenyl)-6-fluoro-[1,2,4]triazolo[4,3-a]pyridine(Intermediate 31b)

Hexachloroethane (3.47 g, 14.68 mmol) was added portionwise at RT to astirred mixture of Intermediate 31a (1.95 g, 7.34 mmol),triphenylphosphine (3.85 g, 14.68 mmol), and triethylamine (4.12 mL,29.36 mmol) in anhydrous THF (60 mL). The reaction mixture was stirredat RT for 3.5 h. The resulting suspension was filtered, washing thesolid with Et₂O. The filtrate was concentrated in vacuo and theresultant residue purified by FCC using SCX-2 cartridge. The cartridgewas washed with MeOH and the product was eluted with 2M NH₃ in MeOH togive the title compound (1.81 g, quantitative) as a fawn coloured solid.LCMS (Method 3): Rt 2.96 min, m/z 248 [MH⁺].

c.(1S,4R)-4-[3-(2-Chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 31c)

Sodium hydride (60% in mineral oil, 840 mg, 21.9 mmol) was addedportionwise to a stirred solution of Intermediate 1d (1.19 g, 7.31 mmol)in anhydrous DMF (30 mL) at RT under an argon atmosphere. Intermediate31b (1.81 g, 7.31 mmol) was then added, and stirring at 60° C. wascontinued for 1.5 h. After cooling, the reaction mixture was quenched bycareful addition of a saturated aqueous solution of NH₄Cl and extractedwith EtOAc (×2). The combined organic layers were washed with brine,dried (MgSO₄) and concentrated in vacuo. The resultant residue waspurified by FCC, using 0-10% MeOH in DCM to afford the title compound(1.48 g, 52%) as a brown foam. LCMS (Method 3): Rt 0.42 and 2.33 min,m/z 391. [MH⁺].

d.1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Example 31)

A mixture of Intermediate 26a (340 mg, 0.95 mmol), Intermediate 31c (372mg, 0.95 mmol), and DIPEA (248 μL, 1.43 mmol) in dioxane (5 mL) wasstirred at 70° C. for 18 h. After cooling to RT, the reaction mixturewas partitioned between DCM and water. The organic layer was driedthrough a phase separator and then concentrated in vacuo. The resultantresidue was purified by FCC, using 0-10% MeOH in DCM to afford the titlecompound (536 mg, 94%) as a brown solid. An aliquot of the compound thusobtained (100 mg) was further purified by MDAP (Method 7) to afford thetitle compound (45 mg). LCMS (Method 5): Rt 4.08 min, m/z 600 [MH⁺]. ¹HNMR (400 MHz, DMSO): 1.20 (9H, s), 1.81-2.19 (4H, m), 3.66 (2H, d, J=6.1Hz), 3.93 (2H, t, J=6.0 Hz), 4.78-4.84 (1H, m), 4.98 (1H, br s), 5.51(1H, t, J=4.3 Hz), 6.05 (1H, s), 7.06 (1H, d, J=8.6 Hz), 7.23-7.30 (1H,m), 7.32-7.38 (4H, m), 7.60 (1H, td, J=7.5, 1.3 Hz), 7.68 (1H, td,J=7.7, 1.9 Hz), 7.73 (2H, td, J=7.5, 1.3 Hz), 7.82-7.92 (2H, m), 8.17(1H, s).

Example 321-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaFormate Salt

A mixture of Example 31 (100 mg, 0.17 mmol), methanesulfonyl chloride(38 μL, 0.33 mmol), and DIPEA (87 μL, 0.50 mmol) in DCM (1 mL) wasstirred at RT 45 min. Additional amount of methanesulfonyl chloride (20μL) was added, and stirring at RT was continued for 20 min. The reactionmixture was diluted with DCM, washed with water (×2) followed by brine,dried through a phase separator and concentrated in vacuo. The resultantresidue was dissolved in THF (1 mL) and treated with morpholine (73 μL,0.83 mmol). Additional amount of morpholine (73 μL, 0.83 mmol) and THF(1 mL) was added, and the reaction mixture was heated at 60° C. for 18h. After cooling, the volatiles were concentrated in vacuo and theresultant residue was purified by MDAP (Method 7) to afford the titlecompound (46 mg, 41%) as an off white solid. LCMS (Method 5): Rt 3.50min, m/z 669 [MH⁺]. ¹H NMR (400 MHz, DMSO): 1.20 (9H, s), 1.83-2.19 (4H,m), 2.35-2.41 (4H, m), 2.61 (2H, t, J=7.1 Hz), 3.54 (4H, t, J=4.6 Hz),3.99 (2H, t, J=7.1 Hz), 4.79-4.88 (1H, m), 5.52 (1H, t, J=4.2 Hz), 6.03(1H, s), 6.94 (1H, d, J=8.6 Hz), 7.24-7.31 (1H, m), 7.32-7.39 (4H, m),7.69 (1H, td, J=7.7, 1.8 Hz), 7.68 (1H, td, J=7.7, 1.8 Hz), 7.72-7.78(2H, m), 7.84-7.92 (2H, m), 8.18 (1H, s), 8.22 (1H, s).

Example 331-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea

a. (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (Intermediate 33a)

A solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.5 g, 3.26mmol) in EtOAc (10 mL) was treated with aqueous NaOH (1M, 5.87 mmol),followed by 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol), andthe reaction mixture was stirred at RT for 1 h. The mixture waspartitioned between EtOAc (10 mL) and water (2×10 mL). The organic layerwas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by FCC, using 0-100% EtOAc in cyclohexane to afford the titlecompound as a pale orange gum (0.915 g, 86%). LCMS (Method 3): Rt 3.88min, m/z 328/330 [MH⁺].

b.1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea(Example 33)

A solution of intermediate 33a (70 mg, 0.21 mmol), intermediate 26d (90mg, 0.21 mmol), and DIPEA (55 μL, 0.32 mmol) in dioxane (1 mL) washeated at 70° C. for 18 h. The mixture was concentrated in vacuo and theresidue was purified by MDAP (Method 7) to afford the title compound asa glassy solid (38 mg, 29%). LCMS (Method 5): Rt 4.37 min, m/z 604.2[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.20 (9H, s), 1.83-2.15 (4H, m), 3.56(3H, s), 4.79-4.88 (1H, m), 5.55 (1H, t, J=4.6 Hz), 6.01 (1H, s), 6.86(1H, d, J=8.5 Hz), 7.23-7.29 (1H, m), 7.31-7.37 (4H, m), 7.69-7.79 (3H,m), 7.91 (1H, dd, J 9.7, 0.9 Hz), 7.98 (1H, d, J=2.2 Hz), 8.23 (1H, s).

Example 341-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaPartial Formate Salt

a. Cyclohexanecarboxylic acid N′-(5-fluoro-pyridin-2-yl)-hydrazide(Intermediate 34a)

To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference proceduresee WO 2010 022076, which is incorporated herein by reference in itsentirety; 1.00 g, 7.87 mmol), cyclohexane carboxylic acid (1.21 g, 9.44mmol), and HOBt.H₂O (166 mg, 0.787 mmol) at 0° C. under N₂ was added EDC(1.81 g, 9.44 mmol), then the mixture stirred at 0° C. for 15 min, andat RT for 17 h. Water was added, then the organics isolated, cooled to0° C., then the resulting suspension filtered to leave the titlecompound as a white solid (1.16 g, 62%). ¹H NMR (400 MHz, CDCl₃):1.21-1.38 (3H, m), 1.45-1.55 (2H, m), 1.66-1.73 (1H, m), 1.80-1.96 (4H,m), 2.22 (1H, tt, J 11.6, 3.5 Hz), 6.62-6.66 (2H, m), 7.29 (1H, ddd, J9.2, 7.9, 3.1 Hz), 7.55 (1H, d, J=4.2 Hz), 8.03 (1H, d, J=2.9 Hz).

b. 3-Cyclohexyl-6-fluoro-[1,2,4]triazolo[4,3-a]pyridine (Intermediate34b)

To a solution of Intermediate 34a (1.15 g, 4.83 mmol),triphenylphosphine (2.54 g, 9.67 mmol), and triethylamine (2.68 mL, 19.3mmol) in dry THF (17 mL) at 0° C. under N₂ was added hexachloroethane(2.28 g, 9.67 mmol), and the mixture stirred at 0° C. for 15 min, and atRT for 6 h. Water was added, then the organics washed with brine, dried(MgSO₄) and concentrated in vacuo. Flash chromatography (silica gel,0-100% EtOAc in cyclohexane) gave the title compound as an off-whitesolid (330 mg, 31%). ¹H NMR (400 MHz, CDCl₃): 1.36-1.55 (3H, m),1.78-2.00 (5H, m), 2.05-2.14 (2H, m), 2.97 (1H, tt, J=11.5, 3.5 Hz),7.16 (1H, ddd, J=10.0, 7.5, 2.3 Hz), 7.76 (1H, dd, J=10.0, 4.9, 0.9 Hz),7.85 (1H, ddd, J=3.5, 2.2, 0.9 Hz).

c.(1S,4R)-4-(3-Cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 34c)

An opaque brown solution of Intermediate 1d (171 mg, 1.05 mmol) andsodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol) in dry DMF (2mL) was stirred at RT under Argon for 30 min. Intermediate 34b (219 mg,1.00 mmol) was added, and the resulting dark solution stirred at 60° C.for 2 h. The cooled solution was concentrated in vacuo, redissolved inMeOH (2 mL), applied to an SCX-2 cartridge, and washed with MeOH. Theproduct was eluted with 2M NH₃ in MeOH; concentration in vacuo left abrown oil. Flash chromatography (silica 25 g, 2-10% [2M NH₃ in MeOH] inDCM) gave a yellow oil. Freeze-drying from MeCN-water (1:2, 3 mL) leftthe title compound as a pale yellow solid (203 mg, 56%). LCMS (Method3): Rt 2.29 min, m/z 363 [MH⁺].

d.1-[5-tert-Butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 34d)

A brown solution of Intermediate 26a (94.2 mg, 0.263 mmol), Intermediate34c (90.6 mg, 0.250 mmol), and DIPEA (0.054 mL, 0.31 mmol) in drydioxane (3 mL) was stirred at 75° C. for 16 h. The cooled solution wasconcentrated in vacuo, suspended in water (3 mL) and extracted with DCM(2×3 mL). The combined organics were passed through a hydrophobic fritand concentrated in vacuo to leave a dark brown oil. Flashchromatography (silica gel, 3-9% MeOH in DCM) gave a pale yellow solid.MDAP (Method 7) gave an off-white solid (72 mg, 50%). LCMS (Method 5):Rt 3.98 min, m/z 572.4 [MH⁺].

e.1-[5-tert-Butyl-2-(2-morpholin-4-yl-ethyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaPartial Formate Salt (Example 34)

A solution of Intermediate 34d (71 mg, 0.12 mmol), mesyl chloride (29mg, 0.25 mmol), and DIPEA (0.065 mL, 0.37 mmol) in DCM (2 mL) wasstirred at 0° C. for 30 min. Water (2 mL) and sat. aq. NaHCO₃ solution(2 mL) were added. The aqueous was extracted with DCM (2 mL), then thecombined organics passed through a hydrophobic frit and concentratedunder vacuum to leave a pale yellow gum. The gum was dissolved in DMF (1mL), and morpholine (0.054 mL, 0.62 mmol) was added, and then stirred at75° C. for 16 h. The cooled solution was concentrated in vacuo,redissolved in MeOH (1 mL), applied to an SCX-2 cartridge (5 g) andwashed with MeOH. The product was eluted with 2M NH₃ in MeOH;concentration in vacuo left a yellow gum. Prep HPLC (Gemini C18, 10-60%MeCN in water, 0.1% HCO₂H, 20 min) and freeze-drying of the desiredfractions gave a white solid (14.9 mg, 19%). LCMS (Method 5): Rt 3.46min, m/z 641.4 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO: 1.20 (9H, s), 1.27-1.38(1H, m), 1.44-1.55 (2H, m), 1.58-1.77 (3H, m), 1.80-1.86 (2H, m),1.92-2.21 (6H, m), 2.39 (4H, t, J=4.4 Hz), 2.62 (2H, t, J=7.1 Hz), 3.29(1H, tt, J=11.3, 3.7 Hz), 3.54 (4H, t, J=4.5 Hz), 4.00 (2H, t, J=7.1Hz), 4.88 (1H, td, J=8.4, 5.7 Hz), 5.59 (1H, t, J=4.3 Hz), 6.03 (1H, s),7.03 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.8, 2.1 Hz), 7.31 (1H, td,J=7.1, 2.0 Hz), 7.35-7.43 (3H, m), 7.69 (1H, dd, J=9.8, 0.8 Hz), 8.23(1H, d, J=2.0 Hz), 8.31 (1H, s), 8.33 (0.3H, s).

Example 351-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea

a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-propan-1-ol (Intermediate 35a)

A solution of 4,4-dimethyl-3-oxo-pentanenitrile (0.7 g, 5.58 mmol) inethanol (IMS grade, 5 mL) was treated with 3-hydrazino-propan-1-oldihydrochloride (1 g, 6.13 mmol), followed by cone. HCl (0.05 mL), andthe reaction mixture was heated at reflux for 18 h. The mixture wasconcentrated in vacuo and the residue was purified by FCC, using 0-10%[2M NH₃ in MeOH] in DCM to afford the title compound as a white gummysolid (0.94 g, 85%). LCMS (Method 3): Rt 0.42 min, m/z 198 [MH⁺].

b. [5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloroethyl ester (Intermediate 35b)

A solution of Intermediate 35a (0.94 g, 4.76 mmol) in EtOAc (15 mL) wastreated with aqueous NaOH (1M, 8.58 mmol), followed by2,2,2-trichloroethyl chloroformate (0.79 mL, 5.72 mmol) and stirred atRT for 1.5 h. The two layers were separated, and the organic layer waswashed with water (2×10 mL), dried (MgSO₄), filtered and concentrated invacuo to afford the title compound as a white solid (1.12 g, 63%). LCMS(Method 3): Rt 3.72 min, m/z 372/374 [MH⁺].

c.1-(5-tert-Butyl-2-(3-hydroxy-propyl)-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-urea(Example 35)

A mixture of Intermediate 35b (200 mg, 0.54 mmol), Intermediate 26d (228mg, 0.54 mmol), and DIPEA (140 μL, 0.80 mmol) in dioxane (2 mL) wasstirred at 70° C. for 18 h. The reaction mixture was cooled to RT,diluted with DCM (10 mL), and washed with water (2×10 mL). The aqueouslayer was extracted with DCM, and the combined organics were passedthrough a phase separator and concentrated in vacuo and the resultantresidue was purified by FCC, using 0-5% [2M NH₃ in MeOH] in DCM toafford the title compound (270 mg, 76%). A 50 mg sample of this waspurified by MDAP (Method 7) to afford the title compound as a glassysolid (17 mg). LCMS (Method 5): Rt 4.24 min, m/z 648.4 [MH⁺]. ¹H NMR(400 MHz, d₆-DMSO): 1.20 (9H, s), 1.79-1.87 (2H, m), 1.88-2.14 (4H, m),3.41 (2H, t, J=5.9 Hz), 3.91 (2H, t, J=7.2 Hz), 4.58 (1H, br s),4.79-4.87 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.03 (1H, s), 6.93 (1H, d,J=8.8 Hz), 7.23-7.29 (1H, m), 7.32-7.38 (4H, m), 7.69-7.79 (3H, m), 7.91(1H, dd, J=9.6 Hz, 0.9 Hz), 7.98 (1H, d, J=1.7 Hz), 8.17 (1H, s).

Biological Assays.

P38alpha Enzyme Inhibition Assay.

The inhibitory activity of compounds was determined using anAlphascreen® (Perkin Elmer) based kinase activity assay. Kinasereactions consisted of 25 mM HEPES pH 7.5, 10 mM MgCl₂, 100 M Na₃VO₄, 2mM DTT, 0.05 mg/ml Tween 20, 100 pM p38alpha (Invitrogen, PV3304), 1%DMSO and 0.3 μg/ml ATF-2 fusion protein (New England Biolabs, 9224).Compounds were incubated under these conditions for 2 hours, at 25° C.,prior to the initiation of the kinase activity by the addition of the250 μM ATP. Reaction volumes were 20 uL. After 1 hr at 25° C. reactionswere stopped by the adding 10 uL of 25 mM HEPES pH 7.5 containing 62.5mM EDTA, 0.05% Triton X-100, 10% BSA and 0.83 ng/uL anti-phospho-ATF2antibody (Abcam, ab28812). Detection was performed by measuringluminescence following the addition of Alphascreen Donor beads (PerkinElmer 6765300) and Protein A Alphascreen Acceptor beads (Perkin Elmer6760137), both at a final concentration of 20 ug/ml. IC₅₀ values weredetermined from concentration-response curves. Results are shown in thefollowing Table:

Example p38α inhibition 1 ++++ 2 ++++ 3 ++++ 4 ++++ 5 ++++ 6 ++ 7 ++++ 8++++ 9 ++++ 11 ++++ 12 ++++ 14 +++ 15 ++++ 16 ++++ 17 ++++ 18 ++++ 19++++ 20 ++ 21 ++++ 22 ++++ 23 ++++ 24 ++++ 25 ++++ 26 ++++ 27 ++++ 28++++ 29 ++++ 30 ++++ 31 ++++ 32 ++++ 33 ++++ 34 ++++In the table above, p38α binding potencies (IC₅₀ values) are indicatedas follows: 7000 to 500 nM, ‘+’; 500 to 100 nM, ‘++’; 100 to 10 nM‘+++’; <10 nM, ‘++++’.LPS-Stimulated PBMC TNFα Release Assay.

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from healthyhuman volunteer blood using a standard density gradient centrifugationtechnique. Citrated blood was placed onto Histopaque™ and centrifuged.The PBMCs were removed from the density gradient interface and washed inphosphate buffered saline (PBS). The PBMCs were suspended in RPMI 1640medium (without serum), dispensed into a 96-well plate and incubated at37° C. for 3 h in a humidified incubator. After incubation, the mediumwas replaced (with medium containing 1% foetal bovine serum), and theplate incubated at 37° C., for 1 h, in the presence of test compound orthe appropriate vehicle. LPS (10 ng/ml), or an appropriate vehiclecontrol, was then added to the cells, and the plate returned to theincubator for 18 h. Cell-free supernatants were removed and assayed forTNFα levels using an ELISA kit from R&D Systems.

A dose response curve to each test compound was performed and the effectof compound in each experiment was expressed as a percentage inhibitionof the control TNFα release. Dose response curves were plotted andcompound potency (IC₅₀) was determined. Compounds were tested in atleast three separate experiments. Results are shown in the followingTable:

Example numbers p38α inhibition 1, 2, 3, 4, 7, 8, 9, 11, 14, 15, 23, 26,27, 28, 29, 30, ++++ 31, 32, 33, 34 5, 10, 12, 18, 19, 22 +++ 13, 17 ++In the table above, p38α potencies (IC₅₀ values) are indicated asfollows: >1000 nM, ‘+’; 1000 to 100 nM, ‘++’; 100 to 10 nM, ‘+++’; <10nM, ‘++++’. All compounds tested exhibited IC₅₀ values <1000 nM.Pre-Clinical Mouse Model of COPD—Tobacco Smoke Induced PulmonaryInflammation.

Previous studies have established that the number of inflammatory cellsrecovered by bronchoalveolar lavage (BAL) is significantly elevated 24 hfollowing the final of four consecutive daily tobacco smoke (TS)exposures. This timepoint may be used in the described model.

Protocols for the exposure of mice to TS, obtaining bronchoalveolarlavage fluid (BALF) and preparation of cytospin slides for differentialcell counts are as outlined below.

Daily Exposure of Mice to TS for 4 Consecutive Days.

In this exposure protocol, mice are exposed in groups of 5 in individualclear polycarbonate chambers (27 cm×16 cm×12 cm). The TS from thecigarettes is allowed to enter the exposure chambers at a flow rate of100 ml/min. In order to minimise any potential problems caused byrepeated exposure to a high level of TS, the exposure of the mice to TSis increased gradually over the exposure period to a maximum of 6cigarettes. The exposure schedule used over the four days is as follows:

Day 1: 5 cigarettes (approximately 25 min exposure) Day 2: 7 cigarettes(approximately 35 min exposure) Day 3: 9 cigarettes (approximately 45min exposure) Day 4: 9 cigarettes (approximately 45 min exposure)A further group of mice are exposed to air on a daily basis forequivalent lengths of time as controls (no TS-exposure).Bronchoalveolar Lavage (BAL) Analysis.

Bronchoalveolar lavage is performed as follows: the trachea iscannulated using a 10 mm long Luer-fitting stainless steel cannula.Phosphate buffered saline (PBS) is used as the lavage fluid. A volume of0.4 ml is gently instilled and withdrawn 3 times, using a 1 ml syringeand then placed in an Eppendorf tube and kept on ice prior to subsequentdeterminations.

Cell Counts:

Lavage fluid is separated from cells by centrifugation and thesupernatant decanted and frozen for subsequent analyses. The cell pelletis re-suspended in a known volume of PBS and total cell numberscalculated by counting a stained (Turks stain) aliquot under amicroscope using a haemocytometer.

Differential Cell Counts are Performed as Follows:

The residual cell pellet is diluted to approximately 10⁵ cells per ml. Avolume of 500 μl is placed in the funnel of a cytospin slide andcentrifuged for 6 min at 800 rpm, RCF=72.26×g (Shandon Cytospin 3). Theslide is air-dried and stained using Wrights/Giemsa stain as per theproprietary instructions. When dried and cover-slipped, differentialcell counts are performed using light microscopy. Approximately fourhundred cells are counted by an unbiased operator using lightmicroscopy. Cells are differentiated using standard morphometrictechniques.

Drug Treatment

Rodents such as mice and rats are obligate nose breathers, thus oraldelivery of test materials (such as therapeutic agents) for inhalationwill not produce good lung exposure. As a consequence, delivery oftherapeutic agents to the lungs in rodents is generally achieved byintranasal, intratracheal or inhalation by either nose-only or wholebody aerosol exposure.

Nose-only or whole body aerosol exposure methods utilize large amountsof test material and are generally reserved for inhalation toxicologystudies rather than more routine pharmacological efficacy studies.Intratracheal administration is a very efficient delivery method asalmost all of the test material is delivered to the lungs but is aninvasive technique. For studies in the mouse particularly, it is alsotechnically demanding as the diameter of the trachea is small. Theintranasal route is less invasive than the intratracheal route and so isparticularly suitable for repeat dosing studies such as the four daymouse model described. Following intranasal administration, ˜50% of thedose administered is delivered to the lungs (see Eyles J E, Williamson ED and Alpar H O. 1999, Int J Pharm, 189(1):75-9), which is incorporatedherein by reference in its entirety.

As a surrogate route for oral inhalation, mice are dosed intra-nasallywith vehicle (0.2% tween 80 in saline) containing test compound. Thecontrol groups of mice receive vehicle 1 hr prior to being exposed toair or TS.

Data Management and Statistical Analysis.

All results are presented as individual data points for each animal, andthe mean value is calculated for each group. Since tests for normalityare positive, the data are subjected to a one-way analysis of variancetest (ANOVA), followed by a Bonferroni correction for multiplecomparisons in order to test for statistically significant differencesbetween treatment groups. A “p” value of <0.05 is considered to bestatistically significant. Percentage inhibitions are automaticallycalculated within Excel spreadsheets for the cell data using the formulabelow:

${\%\mspace{14mu}{Inhibition}} = {( {1 - ( \frac{{{Treatment}\mspace{14mu}{group}\mspace{14mu}{result}} - {{air}\mspace{14mu}{group}\mspace{14mu}{result}}}{{{TS}\mspace{14mu}{vehicle}\mspace{14mu}{group}\mspace{14mu}{result}} - {{air}\mspace{14mu}{group}\mspace{14mu}{result}}} )} ) \times 100}$Inhibition data for other parameters are calculated manually using theabove formula.

Compounds of the invention may be tested in the reported tobacco inducedpulmonary inflammation model to evaluate their anti-inflammatory effectin an animal model of COPD.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

The invention claimed is:
 1. A compound represented by formula (I) or apharmaceutically acceptable salt thereof:

wherein; W is N or O, wherein N is substituted with hydrogen, C₁-C₆alkyl, or C₃-C₅-cycloalkyl; Y is a group —S(O)_(p)— wherein p is 0, 1,or 2; a group —O(CR³R⁴)—; a group —(CR⁵R⁶)_(n)—; a group —NR⁷—; a group—OC(O)—; a group —OC(O)NH—; or a group —OC(O)O—; R³, R⁴, R⁵, and R⁶ areeach independently hydrogen, fluorine, or C₁-C₆ alkyl; or, respectively,R³ and R⁴, or R⁵ and R⁶ may form, together with the carbon atom to whichthey are attached, a 3-6 membered saturated carbocyclic monocyclic ringoptionally substituted with a C₁-C₆ alkyl group, hydroxyl group, orhalogen; n is 0, 1, 2, or 3; R⁷ is hydrogen, C₁-C₆ alkyl, or C₃-C₇cycloalkyl, wherein such C₁-C₆ alkyl, or C₃-C₇ cycloalkyl are optionallysubstituted with a C₁-C₃ alkyl group, C₃-C₆ cycloalkyl group, hydroxylgroup, cyano group, or halogen; R¹ is a group of formula (IIa), (IIb),or (IIc);

wherein R⁸ is —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —NR^(A)R^(B),—N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B), or —R^(C); R^(A) and R^(B)are at each occurrence independently hydrogen, C₁-C₆ alkyl, or C₃-C₇cycloalkyl, said C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionallysubstituted by a C₁-C₃ alkyl group, C₃-C₇cycloalkyl group, —OR^(D),—SR^(D), —NR^(E)R^(F), —CN, or halo; alternatively, R^(A) and R^(B) mayform, together with the nitrogen atom to which they are attached, a 5-11membered saturated monocyclic or bicyclic ring system in which said5-11-membered saturated monocyclic or bicyclic ring is optionallysubstituted by one or more of —OR^(D), —CN, halo, C₁-C₆ alkyl, or C₃-C₇cycloalkyl, wherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl may beoptionally substituted by a C₁-C₃ alkyl group, C₃-C₇cycloalkyl group,—OR^(D), —CN or halo; and wherein, optionally, said 5-11-memberedsaturated monocyclic or bicyclic ring contains a further heteroatomwhich is oxygen or nitrogen, said nitrogen atom optionally substitutedby C₁-C₆ alkyl or C₃-C₆ cycloalkyl wherein any of said C₁-C₆ alkyl orC₃-C₆ cycloalkyl may be optionally substituted by a C₁-C₆ alkyl group,C₃-C₇ cycloalkyl group, —OR^(D), —CN, or halo; R^(c) is at eachoccurrence independently hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl,said C₁-C₆ alkyl and C₃-C₆ cycloalkyl being optionally substituted by aC₁-C₃ alkyl group, OR^(D), CN, or halo; R^(D) is at each occurrenceindependently hydrogen, —CH₃, or —C₂H₅; R^(E) and R^(F) are at eachoccurrence independently hydrogen, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl,said C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by aC₁-C₃ alkyl group, C₃-C₇cycloalkyl group, —OR^(D), —SR^(D), —CN or halo;or R^(E) and R^(F) may form, together with the nitrogen atom to whichthey are attached, a 5-7 membered saturated ring system in which said5-7-membered saturated ring is optionally substituted by one or more of—OR^(D), —CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, said C₁-C₆ alkyland C₃-C₇ cycloalkyl being optionally substituted by a C₁-C₃ alkylgroup, C₃-C₇cycloalkyl group, —OR^(D), —CN or halo; and wherein,optionally, said 5-7-membered saturated ring contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl wherein any of said C₁-C₆alkyl or C₃-C₆ cycloalkyl may be optionally substituted by a C₁-C₆ alkylgroup, C₃-C₇ cycloalkyl group, —OR^(D), —CN, or halo; R²⁶ is hydrogen,—CH₃, or —C₂H₅; X₁ and X₂ are each independently a group —(CH)— or anitrogen atom; R⁹ and R¹⁰ are independently, C₁-C₆ alkyl, C₃-C₆cycloalkyl, phenyl which is optionally substituted, 5- or 6-memberedmonocyclic heteroaryl which is optionally substituted, or a group offormula (IIIa) or (IIIb):

wherein q is 1 or 2; and R²⁴ and R²⁵ are independently hydrogen or C₁-C₆alkyl, or R²⁴ and R²⁵ taken together with the nitrogen to which they areattached form a 6-membered heterocyclic ring optionally containing afurther heteroatom selected from N and O; R¹¹, R¹², and R¹³ areindependently hydrogen, C₁-C₆ alkyl, or halogen; A is a divalentcycloalkylene radical having 5, 6 or 7 ring atoms; said cycloalkylenering being attached to W and Y, and fused to a phenyl ring or to amonocyclic heteroaryl ring having 5 or 6 ring atoms, such phenyl orheteroaryl ring being optionally substituted by one or two groups R²⁷;R²⁷ is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, halogen, and cyano; R² is a group of formula(IVa), (IVb) or (IVc):

wherein R¹⁴ is —F, —CH₂OMe, or —CF₂CF₃; R¹⁵ and R¹⁶ are independently—CH₃ or —C₂H₅; R¹⁷ is lone electron pair, hydrogen, —CF₃,—NR^(E1)R^(F1), —(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), aryl, orheteroaryl wherein any of such —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl, or heteroaryl may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, or halo; or R¹⁷ isa group of formula (V):

wherein R²⁰ is —F, —CH₃, —C₂H₅, —CH₂OH, —CH₂OMe, —CF₂CF₃, —CH₂SCH₃,—SCH₃ or —SC₂H₅; R²¹ is —CH₃ or —C₂H₅; or R²⁰ and R²¹ may form, togetherwith the carbon atom to which they are attached, a 3-7-memberedmonocyclic ring; R^(E1) and R^(F1) are each independently C₁-C₆ alkyloptionally substituted by a C₁-C₃ alkyl group, —OR^(G), —CN, or halo;alternatively, R^(E1) and R^(F1) may form, together with the nitrogenatom to which they are attached, a 5-11-membered saturated monocyclic orbicyclic ring system in which said 5-11-membered saturated monocyclic orbicyclic ring is optionally substituted by one or more of —OR^(G), —CN,halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl and C₃-C₇cycloalkyl being optionally substituted by a C₁-C₃ alkyl group,C₃-C₇cycloalkyl group, —OR^(G), —CN, or halo; and wherein, optionally,said 5-11-membered saturated monocyclic or bicyclic ring contains afurther heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R^(G) isindependently at each occurrence hydrogen, —CH₃, or —C₂H₅; R¹⁸ is loneelectron pair, hydrogen, aryl, heteroaryl, —(C₁-C₆alkyl),—(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), or (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl); wherein any of such aryl, heteroaryl, —(C₁-C₆alkyl),—(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), or (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl) may be optionally substituted by a —CN, —OH, halo,—COOR^(M), C₁-C₆alkyl, C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl), —S—(C₃-C₆cycloalkyl),—NR^(H)R^(J), —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J)),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl); wherein any of saidC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl) and (C₅-C₇heterocycloalkyl)carbonylportion in the above listed groups may be optionally substituted by aC₁-C₆ alkyl group, C₃-C₇ cycloalkyl group, —OR^(M) or halo; R^(H) andR^(J) are at each occurrence independently hydrogen, C₁-C₆ alkyl, orC₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a C₁-C₃ alkyl group, —OR^(M), —CN, or halo;alternatively, R^(H) and R^(J) may form, together with the nitrogen atomto which they are attached, a 5-11 membered saturated monocyclic orbicyclic ring system in which said 5-11-membered saturated monocyclic orbicyclic ring is optionally substituted by one or more of —OR^(M), —CN,halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl and C₃-C₇cycloalkyl being optionally substituted by a C₁-C₃ alkyl group,C₃-C₇cycloalkyl group, —OR^(M), —CN, or halo; and wherein, optionally,said 5-11-membered saturated monocyclic or bicyclic ring contains afurther heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein anyof said C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted bya C₁-C₆ alkyl group, C₃-C₇ cycloalkyl group, —OR^(M), —CN, or halo;and/or R^(H) and R^(J) may be linked to one carbon atom of the—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)-portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms; R^(L) is at each occurrence independently hydrogen,C₁-C₆ alkyl, or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkylbeing optionally substituted by a C₁-C₃ alkyl group, —OR^(M), —CN, orhalo; R^(M) is at each occurrence independently hydrogen, C₁-C₄ alkyl,or C₃-C₆ cycloalkyl, said C₁-C₄ alkyl or C₃-C₆ cycloalkyl beingoptionally substituted by hydroxyl, —CN, or halo; R¹⁹ is hydrogen, —CF₃,—NR^(E)R^(F), —(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), aryl, orheteroaryl wherein any of such —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl, or heteroaryl may be optionallysubstituted by a C₁-C₆ alkyl group, C₃-C₇ cycloalkyl group, or halo; orR¹⁹ is a group of formula (V):

wherein R²⁰, R²¹, R^(E) and R^(F) are as above defined; z¹, z², z³, andz⁴ are independently selected from the group consisting of C, N, S, O,—CH—, and —NH—, in such a combination that the resulting ring formed isan aromatic system; T is —N═ or —CR²⁸═; R²⁸ is H, halo, —CH₃, or —CN;R²² is H, halo, —CH₃, or —CN; with the provisos that: (1) when z¹=—CH—,z²=—C—, z³=—O—, z⁴=—N—, R¹⁸ is an electron lone pair, R¹⁷ is a group offormula (V), and R²¹ is —CH₃ or —C₂H₅; then R²⁰ is —F, —CH₂OMe, or—CF₂CF₃; (2) when z¹=—CH—, z²=—C—, z³=—N—, z⁴=—N—, R¹⁷ is a group offormula (V), R²¹ is —CH₃ or —C₂H₅ and R²⁰ is —CH₃, —C₂H₅; —CH₂OH,—CH₂SCH₃, —SCH₃, or —SC₂H₅, and R₁₈ is a phenyl ring; then: (a) saidphenyl ring is substituted by a group which is selected from the groupconsisting of —CN, —COOR^(M), C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl), —S—(C₃-C₆cycloalkyl),—NR^(H)R^(J), —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S—(C₂-C₆alkylene)-NR^(H)R^(J), —S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)NR^(H)R^(J),—C(O)NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J)—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl); wherein any of suchC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl), and(C₅-C₇heterocycloalkyl)carbonyl portion in the above listed groups maybe optionally substituted by a C₁-C₆ alkyl group, C₃-C₇ cycloalkylgroup, —OR^(M), or halo; or (b) said phenyl ring is substituted by agroup which is —(C₁-C₆alkylene)-NR^(H)R^(J) or—O—(C₂-C₆alkylene)-NR^(H)R^(J) wherein R^(H) and R^(J), which are notboth hydrogen, are at each occurrence independently hydrogen, C₁-C₆alkyl, or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl beingsubstituted by —OR^(M), —CN or halo; alternatively, R^(H) and R^(J) mayform, together with the nitrogen atom to which they are attached, a 5-11membered saturated monocyclic or bicyclic ring system in which said5-11-membered saturated monocyclic or bicyclic ring is substituted byone or more of —OR^(M), —CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl,said C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by aC₁-C₃ alkyl group, C₃-C₇cycloalkyl group, —OR^(M), —CN, or halo; andwherein, optionally, said 5-11-membered saturated monocyclic or bicyclicring contains a further heteroatom which is oxygen or nitrogen, saidnitrogen atom optionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl,wherein any of said C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionallysubstituted by a C₁-C₆ alkyl group, C₃-C₇ cycloalkyl group, —OR^(M),—CN, or halo; or (c) said phenyl ring is substituted by a groupC₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is substituted by a C₁-C₆alkyl group, C₃-C₇ cycloalkyl group, —OR^(M), or halo; or (d) saidphenyl ring is substituted by a group —OR^(L) wherein R^(L) is C₁-C₆alkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl beingoptionally substituted by a C₁-C₃ alkyl group, —OR^(M), —CN, or halo; or(e) said phenyl ring is substituted by a group C₁-C₆ alkyl which issubstituted by a C₃-C₇ cycloalkyl group, OR^(M), or halo; and (3) whenR¹⁹ is a morpholine ring and T is —CR²⁸═ or —N═; then R²², if present atposition ortho to group T of the aromatic ring, is —CH₃ or —CN.
 2. Acompound or pharmaceutically acceptable salt thereof according to claim1, which is a compound of formula (Ia) in which the carbon stereogeniccenter on the cycloalkylene portion of ring A which is linked to group Wand identified with number (1) herebelow, possesses the absoluteconfiguration herebelow represented:


3. A compound or pharmaceutically acceptable salt thereof according toclaim 1, which is a compound of formula (Ib) in which the carbonstereogenic centers on the cycloalkylene portion of ring A which arelinked to group W and Y and identified, respectively, with numbers (1)and (2) herebelow, possess the absolute configuration herebelowrepresented:


4. A compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein A is group represented by one of the followingformulae:


5. A compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein W is NH or O.
 6. A compound or pharmaceuticallyacceptable salt thereof according to claim 1, wherein Y is —S(O)_(p)—,—O(CR³R⁴)_(n)—, —(CR⁵R⁶)_(n)—, or —NR⁷—; p is zero, and n is 0, 1, or 2.7. A compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein R² is a group of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N, and R¹⁷ is a group of formula(V):

wherein R²⁰ is —CH₃ or —CH₂OH, R²¹ is —CH₃, and wherein R¹⁸ is phenyl,which is substituted by a group which is —(C₁-C₆alkylene)-NR^(H)R^(J) or—O—(C₂-C₆alkylene)-NR^(H)R^(J) wherein R^(H) and R^(J), which are notboth hydrogen, are at each occurrence independently hydrogen, C₁-C₆alkyl, or C₃-C₆ cycloalkyl, wherein said C₁-C₆ alkyl or C₃-C₆ cycloalkylis substituted by OR^(M), CN, or halo; alternatively, R^(H) and R^(J)may form, together with the nitrogen atom to which they are, attached a5-11 membered saturated monocyclic or bicyclic ring system in which said5-11-membered saturated monocyclic or bicyclic ring is substituted byone or more of OR^(M), CN, halo, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, saidC₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by a C₁-C₃alkyl group, C₃-C₇cycloalkyl group, OR^(M), CN, or halo; and whereinoptionally, said 5-11-membered saturated monocyclic or bicyclic ringcontains a further heteroatom which is oxygen or nitrogen, said nitrogenatom optionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, whereinany of said alkyl or cycloalkyl may be optionally substituted by a C₁-C₆alkyl group, C₃-C₇ cycloalkyl group, OR^(M), CN, or halo; or wherein R¹⁸is phenyl, which is substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is substituted by a C₁-C₆alkyl group, C₃-C₇ cycloalkyl group, OR^(M), or halo; or wherein R¹⁸ isphenyl, which is substituted by a C₁-C₆ alkyl group which is substitutedby a C₃-C₇ cycloalkyl group, —OR^(M), or halo; or wherein R¹⁸ is phenyl,which is substituted by —CN, —O—(C₁-C₆alkyl), —NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —S—(C₂-C₆alkylene)-OR^(M),—(C₃-C₇heterocycloalkyl), wherein any of said C₁-C₆alkyl,—(C₂-C₆alkylene)-, —(C₃-C₇heterocycloalkyl), portion in the above listedgroups may be optionally substituted by a C₁-C₆ alkyl group, C₃-C₇cycloalkyl group, OR^(M), or halo.
 8. A compound or pharmaceuticallyacceptable salt thereof according to claim 1, wherein R² is a group offormula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N, and R¹⁷ is a group of formula(V):

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃, and R¹⁸ is heteroarylring which is optionally substituted by a group(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), which is optionally substitutedby a C₁-C₆ alkyl group, C₃-C₇ cycloalkyl group, OR^(M), or halo; or R¹⁸is heteroaryl ring which is optionally substituted by a group—(C₁-C₆alkylene)-NR^(H)R^(J) or —O—(C₂-C₆alkylene)-NR^(H)R^(J).
 9. Acompound or pharmaceutically acceptable salt thereof according to claim1, wherein R² is a group of formula (IVb):

wherein z¹=—CH—, z²=C, z³ and z⁴ are N, and R¹⁷ is a group of formula(V):

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃, and R¹⁸ is a—(C₁-C₆alkyl) group, optionally substituted by —OH, halo, or—NR^(H)R^(J); or a (C₅-C₇heterocycloalkyl) group or(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) group which may be optionallysubstituted by a C₁-C₆ alkyl group, halo, or —OH.
 10. A pharmaceuticalcomposition, comprising a compound or pharmaceutically acceptable saltthereof according to claim 1, together with one or more pharmaceuticallyacceptable carriers.
 11. A method for the treatment of a disease orcondition which benefits from inhibition of p38 MAP kinase activity,comprising administering an effective amount of a compound orpharmaceutically acceptable salt thereof according to claim 1 to asubject in need thereof.
 12. A method according to claim 11, whereinsaid disease or condition is chronic eosinophilic pneumonia, asthma,COPD, adult respiratory distress syndrome, exacerbation of airwayshyper-reactivity consequent to other drug therapy or airways diseasethat is associated with pulmonary hypertension.